EMULSIONs

1. EMULSIONs DEPARTMENT OF PHARMACEUTICS CHALAPATHI INSTITUTE OF PHARMACEUTICAL SCIENCES Lam,guntur

2. Outline Definition Classification Identification of emulsion Application of emulsion Theory of emulsification Formulation of emulsion Emulsification techniques Reference

3. What is an emulsion dispersed phase continuous phase An emulsion is a thermodynamically unstable system consisting of at least two immiscible liquid phases one of which is dispersed as globules in the other liquid phase stabilized by a third substance called emulsifying agent.

4. Pharmaceutical applications of emulsions: • They can mask the bitter taste and odor of drugs, e.g. castor oil, cod-liver oil etc. • They can be used to prolong the release of the drug thereby providing sustained release action. • Essential nutrients like carbohydrates, fats and vitamins can all be emulsified and can be administered to bed ridden patients as sterile intravenous emulsions. • Emulsions provide protection to drugs which are susceptible to oxidation or hydrolysis. • Intravenous emulsions of contrast media have been developed to assist in diagnosis. • Emulsions are used widely to formulate externally used products like lotions, creams, liniments etc.

5. Classification of emulsions 1. Based on dispersed phase - Simple emulsions Oil in Water (O/W) Water in Oil (W/O) - Multiple emulsions Oil-in-water-in-oil (O/W/O) Water-in-oil-in-water (W/O/W) - Micro emulsions (Globule size is less than 120 nm, they appear to be transparent.) 2. Based on size of liquid droplets 0.2 – 50 mm Macro emulsions (Kinetically Stable) 0.01 – 0.2 mm Micro emulsions (Thermodynamically Stable)

6. SIMPLE EMULSION

7. DIFFERENCE BETWEEN O/W AND W/O EMULSIONS

8. Multiple emulsion W/O/W SYSTEM O/W/O SYSTEM water phase oil phase Also called emulsion within emulsion They are developed with a view to delay the release of an active ingredient. They have three phases. They may be oil-in-water-in-oil (o/w/o) or of water-in-oil-in-water (w/o/w).

9. PREPARATION OF MULTIPLE EMULSIONS (TWO STEP METHOD)

10. MICROEMULSION • They may be defined as dispersions of insoluble liquids in a second liquid that appears clear and homogenous to the naked eye. • They are frequently called solubilised systems because on a macroscopic basis they seem to behave as true solutions. • As in micro emulsions the globule size is less than 120 nm, • they appear to be transparent. • Example: • Etoposide micro emulsion • methotraxate micro emulsion

11. Microemulsions • Microemulsions are thermodynamically stable optically transparent , mixtures of a biphasic oil –water system stabilized with surfactants.

12. Micro emulsion/macro emulsion micro macro • Thermodynamically stable • Droplet size is 10-100nm (transparent) • High surface area (200m2/g) • Kinetically stable • 1-10 microns (opaque) • Low surface area (15m2/g)

13. Pharmaceutical applications of microemulsions • Increase bioavailability of drugs poorly soluble in water. • Topical drug delivery systems • Oral products • It covers the unpleasant taste • Increases absorption rate • O/W Parenteral use emulsion • i/v lipid nutrients • i/m – depot effect for water soluble antigenic material • Topical use : • Washable • Acceptable viscosity • Less greasy

14. To mask the taste • O/W is convenient means of orally administration of water- insoluble liquids • O/W emulsion facilitates the absorption of water-insoluble compounds comparing to their oily solution preparations (e.g. vitamins) • Oil-soluble drugs can be given parentrally in form of oil-in water emulsion. (e.g. Taxol) • Emulsion can be used for external application in cosmetic and therapeutic uses.

15. Identification of emulsion Add drops of water Add drops of water Water distribute Uniformly • DILUTION TEST: • In this test the emulsion is diluted either with oil or water. If the emulsion is o/w type and it is diluted with water, it will remain stable as water is the dispersion medium" but if it is diluted with oil, the emulsion will break as oil and water are not miscible with each other. O/W Emulsion W/O Emulsion

16. Emulsion Emulsion Bulb doesn’t glow with W/O Bulb glows with O/W CONDUCTIVITY TEST water is good conductor of electricity whereas oil is non-conductor. Therefore, continuous phase of water runs electricity more than continuous phase of oil.

17. DYE TEST Dye Solubility test: Water soluble dye (methylene blue) will be taken up by the aqueous phase where as oil soluble dye will be taken by oily phase. When microscopically it is observed that water soluble dye is taken up by the continuous phase ,it is o/w emulsion. If the dye is not taken up by the continuous phase , test is repeated with oil soluble dye.. Coloring of continuous phase confirms w/o emulsion. This test can fail if ionic emulsions are present.

18. Water Soluble Dye Ex. Amaranth Dye water is continuous phase Oil is dispersed phase O/W EMULSION oil is continuous phase water is dispersed phase W/O EMULSION • Water-soluble dye will dissolve in the aqueous phase.

19. Oil Soluble Dye Ex. scarlet water is continuous phase Oil is dispersed phase O/W EMULSION oil is continuous phase water is dispersed phase W/O EMULSION • Oil-soluble dye will dissolve in the oil phase.

20. Fluorescent test Oils give fluorescence under UV light, while water doesn’t. Therefore, O/W emulsion shows spotty pattern while W/O emulsion fluoresces. When a w/o emulsion is exposed to fluorescent light under a microscope the entire field fluorescence. If the fluorescence is spotty, then the emulsion is of o/w-type. However, all oils do not exhibit fluorescence under UV light and thus the method does not have universal application.

21. COCL2/ FILTER PAPER TEST • Filter paper impregnated with CoCl2 and dried appear to be blue but when dipped in o/w emulsion changes to pink. • This test may fail if emulsion unstable or breaks in presence of electrolyte

22. CREAMING TEST • The direction of creaming identifies the emulsion type, if the densities of aqueous and oil phases are known. • Water-in-oil emulsions normally cream downward as oil is usually less dense than water. • Oil-in-water emulsions normally cream upwards.

23. APPLICATIONS OF EMULSIONS • For prolonged action • Taste masking • Improved stability • Parenteral preparation • Enzyme entrapment • Increased Oral bioavailability

24. instability of emulsion • Emulsification is not a spontaneous process and hence emulsions have minimal stability. • Reasons for instability can be understood from the nature of immiscible phases and their interfacial properties. When two immiscible liquids are agitated together polar (aqueous) and non polar (oil) liquids are mixed together one of the liquids forms small droplets and gets dispersed in the other liquid forms an emulsion.

25. When left aside, droplets fuse themselves and finally separate as two layers. This in an indication of instability of an emulsion. • Except in the case of very dilute oil-in-water emulsions (oil hydrosols), which are somewhat stable, the liquids separate rapidly into two clearly defined layers. • The state of instability may be described by the fact that the cohesive force between the molecules of each separate liquid is greater than the adhesive force between the two liquids. • Any attempt to increase the adhesive forces between these phases can produce a stable emulsion. • A system is said to be thermodynamically stable, if it possesses low surface free energy. • The higher the interfacial area, the greater is the interfacial free energy, and hence lower the stability.

26. instability of emulsions Flocculation and creaming Coalescence and breaking (c) Miscellaneous physical and chemical changes (d) Phase inversion.

27. Flocculation • Neighboring globules come closer to each other and form colonies in the continuous phase. This aggregation of globules is not clearly visible. • This is the initial stage that leads to instability. • Flocculation of the dispersed phase may take place before, during or after creaming.

28. The extent of flocculation of globules depends on (a) globule size distribution. (b) charge on the globule surface. (c) viscosity of the external medium. (a) Globule size distribution • Uniform sized globules prevent flocculation. • This can be achieved by proper size reduction process. (b) Charge on the globule surface • A charge on the globules exert repulsive forces with the neighboring globules. • This can be achieved by using ionic emulsifying agent, electrolytes etc.

29. (c) Viscosity of the external medium. • If the viscosity of the external medium is increased, the globules become relatively immobile and flocculation can be prevented. • This can be obtained by adding viscosity improving agents (thickening agents) such as hydrocolloids or waxes. • Floccules slowly move either upward or downward leading to creaming. • Flocculation is due to the interaction of attractive and repulsive forces, whereas creaming is due to density differences in the two phases.

30. Creaming • Creaming is the concentration of globules at the top or bottom of the emulsion. • Droplets larger than 1 mm may settle preferentially to the top or the bottom under gravitational forces. • Creaming may also be observed on account of the difference of individual globules (movement rather than flocs). • It can be observed by a difference in color shade of the layers.

31. It is a reversible process, i.e., cream can be redispersed easily by agitation, this is possible because the oil globules are still surrounded by the protective sheath of the emulsifier. • Creaming results in a lack of uniformity of drug distribution. This leads to variable dosage. Therefore, the emulsion should be shaken thoroughly before use. • Creaming is of two types, upward creaming and downward creaming

32. Upward creaming, is due to the dispersed phase is less dense than the continuous phase. This is normally observed in o/w emulsions. The velocity of sedimentation becomes negative. • Downward creaming occurs if the dispersed phase is heavier than the continuous phase. Due to gravitational pull, the globules settle down. This is normally observed in w/o emulsions. • Since creaming involves the movement of globules in an emulsion, Stokes’ law can be applied. ν = d2 (ρs – ρ0) • 18 η0 • ν= terminal velocity in cm/sec, • d is the diameter of the particle in cm, • ρs and ρ0 are the densities of the dispersed phase and dispersion medium respectively, • g is the acceleration due to gravity and • η0 is the viscosity of the dispersion medium in poise.

33. Creaming is influenced by, • Globule size • Viscosity of the dispersion medium • Difference in the densities of dispersed phase and dispersion medium. Creaming can be reduced or prevented by: 1. Reducing the particle size by homogenization. Doubling the diameter of oil globules increases the creaming rate by a factor of four. 2. Increasing the viscosity of the external phase by adding the thickening agents such as methyl cellulose tragacanth or sodium alginate. • 3. Reducing the difference in the densities between the dispersed phase and dispersion medium. • 4. Adjusting the continuous phase and dispersed phase densities to the same value should eliminate the tendency to cream. • 5. To make densities equal, oil soluble substances such as bromoform, β-bromo naphthalene are added to the oil phase (rarely used technique).

34. COALESCENCE • If the sizes of globules are not uniform, globules of smaller size occupy the spaces between the larger globules. A few globules tend to fuse with each other and form bigger globules. • This type of closed packing induces greater cohesion which leads to coalescence. • In this process, the emulsifier film around the globules is destroyed to a certain extent. This step can be recognized by increased globule size and reduced number of globules.

35. Coalescence is observed due to: • Insufficient amount of the emulsifying agent. • Altered partitioning of the emulsifying agent. • Incompatibilities between emulsifying agents. • Phase volume ratio of an emulsion has a secondary influence on the stability of the product and represents the relative volume of water to oil in emulsion. • At higher ratio (>74% of oil to water), globules are closely packed, wherein small globules occupy the void spaces between bigger globules. • Thus globules get compressed and become irregular in shape, which leads to fusion of adjacent globules. • Ostwald and others have shown that if one attempts to incorporate more than about 74% of oil in an o/w emulsion, the oil globules often coalesce and the emulsion breaks. • This value known as the critical point, is defined as the concentration of the dispersed phase above which the emulsifying agent cannot produce a stable emulsion of the desired type.

36. BREAKING • Separation of the internal phase from the external phase is called breaking of the emulsion. • This is indicated by complete separation of oil and aqueous phases, is an irreversible process, i.e., simple mixing fails. It is to resuspend the globules into an uniform emulsion. • In breaking, the protective sheath around the globules is completely destroyed and oil tends to coalesce.

37. PHASE INVERSION • This involves the change of emulsion type from o/w to w/o or vice versa. • When we intend to prepare one type of emulsion say o/w, and if the final emulsion turns out to be w/o, it can be termed as a sign of instability.

38. FORMULATION OF EMULSION Aqueous phase: purified water Organic phase: arachis oil, cod liver oil, sesame oil, castor oil Emulsifier: acacia,SLS,tween,bentonite Antioxidant: sodium bisulphite,sodium nitrite Preservatives: methyl and propyl paraben

39. Emulsifying agents Emulsifier or surface active agent (SAA) is molecule which has two parts, one is hydrophilic and the other is hydrophobic. Upon the addition of SAA, it tends to form monolayer film at the oil/water interface. Mechanism of action of emulsifying agents: When two immiscible liquids are agitated together so that one of the liquids is dispersed as small droplets in the other. To prevent coalescence between globules, it is necessary to use emulsifying agent.

40. CLASSIFICATION OF EMULSIFYING AGENTS • Natural emulsifying agents from vegetable sources • Natural emulsifying agents from animal sources • Synthetic emulsifying agents • Finally divided emulsifying agents • Auxiliary divided emulsifying agents. • Saponins • Alcohols

41. Properties of an ideal emulsifying agent Reduce the interfacial tension between the two immiscible liquids. Physically and chemically stable, inert and compatible with the other ingredients of the formulation. Completely non irritant and non toxic in the concentrations used. Organoleptically inert i.e. should not impart any colour, odour or taste to the preparation. Form a coherent film around the globules of the dispersed phase and should prevent the coalescence of the droplets of the dispersed phase. Produce and maintain the required viscosity of the preparation.

42. A) NATURAL EMULSIFYING AGENTS FROM VEGETABLE SOURCES • Obtained from vegetable source • Anionic in nature • Produce O/W emulsions • Capable of emulsifying a large number of substances Example: • Acacia • Tragacanth • Agar • Chondrus • Pectin • starch

43. ACACIA • Emulsions formed are O/W. • Stable over wide range of PH. • Soluble in water • Low viscosity that’s why creaming takes place • Should be preserved properly

44. TRAGACANTH • It alone is rarely used as an emulsifying agent because it doesn't reduce interfacial tension. • Produces very coarse and thick emulsion with increase viscosity. • Stable emulsion is produce when use along with acacia.

45. AGAR • Good emulsifying agents because they forms a very coarse and viscous emulsion • Used as thickening agent along with acacia.

46. CHONDRUS • Like agar it is not used as primary emulsifier. • It is used as a thickening agent. • Used along with acacia for the emulsification of cod-liver oil.

47. PECTIN • It is a purified complex carbohydrate obtain from rind of citrus fruit. • It act as a emulsion stabilizer in acacia emulsions. • Mucilage of pectin is prepared before adding it to emulsion. • To prevent lump formation pectin is triturated with small amount of alcohol or glycerol.

48. B) NATURAL EMULSIFYING AGENTS FROM ANIMAL SOURCES • Obtained from animals body. Examples : • Gelatin, • Egg yolk, • Wool fat.

49. GELATIN • Mainly used for the emulsification of liquid paraffin. • Protein in nature • It possesses isoelectronic point. • Prone to bacterial growth • Suitable preservative should be added.

50. EGG YOLK • It itself is an emulsion because of the presence of lecithin and cholesterol • Rarely used in industrial preparations because it is spoiled during transportation. • Used in extemporaneous preparations.