1. What is the relationship between milk and emulsion? PH 201.421

2. Biphasic Liquid dosage forms PH 201.422 Emulsions Liquid in liquid dispersion (Immiscible) Suspensions Solid in liquid suspension (Insoluble) Should have two separate phases

3. EMULSIONS: What are they? An emulsion is a thermodynamically stable two- phase system consisting of at least two immiscible liquids, one of which is dispersed in the form of small droplets throughout the other with the help of an emulsifying agent. Size of droplets - range from around 0.1 to 10 µm in diameter - Larger ones visible with light microscopy Microemulsion: Droplets size range 0.01 to 0.1 m m Macroemulsion: Droplets size range approximately 5 m m. Internal phase or Dispersed phase or Discontinuous phase External phase or Continuous phase PH 201.423

4. 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 – Emulsifying agents can increase the kinetic stability of emulsions greatly so that, once formed, the emulsion does not change significantly over years of storage. PH 201.424

5. Emulsions: Why are they used? Systemic uses Oral Nutrition - triglycerides (e.g. vegetable oils) Means of masking unpleasant flavour Parenteral Nutrition - triglycerides Delivery of drugs poorly soluble in water Site-directed delivery of drugs Necessarily small droplet size, Comparable to chylomicrons Delayed-release (e.g. I.m.) PH 201.425

6. Emulsions: Why are they used? Local uses Skin May be o/w or w/o Applied or rubbed Application of drugs Viscous and remain where applied Emolliency, greasiness, acceptability Called "creams", "lotions" Oral/rectal Constipation Called "emulsions"/"enemas" PH 201.426

7. Examples of emulsions as drug delivery systems Diazepam: Emulsion eliminates pain due to crystallization of a solubilized drug following dilution in the bloodstream Vegetable oils: Delivery of substrates high in metabolic energy Propofol: Liquid anaesthetic dissolved in emulsified oil Fluorocarbons: Artificial blood substitutes PH 201.427

8. Advantages 1. Can mask the bitter taste and odor of drugs - make them more palatable. e.g. castor oil, cod-liver oil etc. 2. Can be used to prolong the release of the drug - sustained action. 3. Essential nutrients like carbohydrates, fats and vitamins can all be emulsified and can be administered to bed ridden patients as sterile intravenous emulsions. 4. Protects drugs against oxidation or hydrolysis. 5. Intravenous emulsions of contrast media have been developed to assist in diagnosis. 6. Emulsions are used widely to formulate externally used products like lotions, creams, liniments etc. PH 201.428

9. Disadvantages 1.Highly unstable 2.Susceptible to temperature and pH changes. 3.Microbial growth and subsequent spoilage is common in emulsions prepared by using natural emulgents. 4.Size of globules is of great concern in parenteral administration PH 201.429

10. Classification PH 201.4210 Emulsions Macro emulsions Multiple emulsions Mini emulsions Micro emulsions Simple emulsions Nano emulsions PIT emulsions Molecular emulsions Micellar emulsions O/W W/O O/W/O W/O/W Primary emulsions / Secondary emulsions /

11. Droplet size and the appearance of emulsions PH 201.4211 MINIEMULSIONS MINIEMULSIONS Macroemulsion Microemulsions

12. Thermodynamic stability of different types of emulsions PH 201.4212

13. ……Types of emulsions Oil in Water emulsions (O/W) Oil is the dispersed phase and water is the dispersion medium. Used mainly for internal/oral use Externally - non greasy creams, lotions and liniments. Cosmetic products as o/w emulsions can easily be removed from the surface of the skin Example: Castor oil emulsion, foundation creams, vanishing creams. Water in oil Emulsions (W/O) Water is the dispersed phase and oil is the dispersion medium Used mainly externally as lotions and creams. Also effective as cleansing cream. Example: Cold creams. PH 201.4213

14. Microscopic view of emulsions PH 201.4214

15. Oil in water emulsion (O/w)Water in oil emulsion (w/o) Water is the dispersion mediumOil is the dispersion medium Oil is the dispersed phaseWater is the dispersed phase Non greasy and easily removable from the skin surface Greasy and not water washable Used externally to provide cooling effect e.g. vanishing cream Used externally to prevent evaporation of moisture from the surface of skin e.g. Cold cream Water soluble drugs are more quickly released from o/w emulsions Oil soluble drugs are more quickly released from w/o emulsions Preferred for formulations meant for internal use as bitter taste of oils can be masked. Preferred for formulations meant for external use like creams. Give a positive conductivity test as water is the external phase which is a good conductor of electricity. Do not give a positive conductivity test as oil is the external phase which is a poor conductor of electricity. PH 201.42 15 Differences between O/W and W/O emulsions

16. Multiple Emulsions Multiple emulsions are primarily used for formulating sustained release dosage forms. Types Oil in water in oil (o/w/o) emulsion Water in oil in water (w/o/w) emulsion PH 201.4216

17. Identification tests for emulsions Since emulsion (o/w or w/o) looks the same in appearance with naked eyes, therefore certain tests have been developed to differentiate between them. They are 1.Dilution test (emulsion can be diluted only with external phase) 2.Dye test (using water or oil soluble dyes) 3.Electrical conductivity test (o/w emulsions conduct electric current) PH 201.4317

18. Identification tests for emulsions…… 4.Fluorescence test (some oils fluoresce under UV light) 5.Cobalt chloride paper test (CoCl 2 blue paper turns pink when hydrated) 6.Depending on the direction of creaming At least two tests should be done to reach a conclusive decision about the identity of the emulsion. PH 201.4318

19. 1. Dilution test PH 201.4319 Dilution Test for oil in water emulsion Dilution test for water in oil emulsion Based on the solubility of external phase of emulsion. - o/w emulsion can be diluted with water. - w/o emulsion can be diluted with oil.

20. 2. Dye Solubility Test Emulsion is mixed with a water soluble dye such as amaranth and observed under the microscope, if the continuous phase appears red and continuous phase colorless, then it is w/o type. Similarly if an oil soluble dye such as Scarlet red or Sudan III is added to an emulsion and the continuous phase appears red, then it w/o emulsion. PH 201.4320 water soluble dye amaranth

21. 3. Electrical Conductivity Test Based on the basic principle that water is a good conductor of electricity. This test will be positive as water is the external phase. An assembly consisting of a pair of electrodes connected to a lamp is dipped into an emulsion. If the emulsion is o/w type, the lamp glows. PH 201.4321

22. ……..Electrical Conductivity Test PH 201.4322 For oil in water emulsion For water in oil emulsion

23. 4. Cobalt Chloride Test When an emulsion is added to a dried filter paper soaked in cobalt chloride solution, it turns from blue to pink, indicating that the emulsion is o/w type. PH 201.4323 Cobalt chloride paper (Dried) Remains same Turns pink If oil is the continuous phase If water is the continuous phase

24. 5. Fluorescence Test If an emulsion on exposure to ultra-violet radiations shows continuous florescence under microscope w/o Spotty fluorescence o/w PH 201.4324 On exposure to UV light Emulsion W/O Emulsion O/W Emulsion

25. 6. Depending on the direction of creaming Most of the oils are lighter than water except clove oil. Creaming is the formation of relatively concentrated emulsion. If creaming occurs at the top of the emulsion - oil is the dispersed phase (O/W) If creaming occurs at the bottom of the emulsion - water is the dispersed phase (W/O) PH 201.4325

26. What is Emulsification? PH 201. 4426 Emulsifier OIL WATER W/O O/W

27. Concept of formulation PH 201. 4427

28. PH 201. 4428 Concept of formulation х

29. Formulation 1.Selection of oily phase - Toxicity of the oil - Desired consistency - Possible chemical incompatibilities For oral emulsions - Mineral oils - Edible vegetable oils PH 201. 4429

30. Formulation….. 2. Phase volume ratio The internal phase concentration will be determined by A. Dosage requirement For O/W emulsions – 31-45% water For W/O emulsions - < 25% water B. Consistency desired PH 201. 4430

31. 3. Other additives in emulsion A.Viscosity builders – To buildup the viscosity of the external phase Eg: Hydrocolloids B. Antimicrobials – To protect against microbial degradation Eg: Benzoic acid, Methyl paraben C. Antioxidants – To protect against rancidity Eg: BHT,BHA, Gallic acid, Propylgallate, Tocopherols. D. Organoleptic additives - To improve palatabilty of emulsion Colour, Flavour and Sweetners. PH 201. 4431 Formulation…..

32. 4. Choice of emulgent Selection based on A.Toxicity B.Chemical incompatibility C.The cost D.Types of emulsion desired E.Shelf life PH 201. 4432

33. PH 201. 4433 HYDROCOLLOIDS Plants Animal Mineral SYNTHETICS Acacia Tragacanth Alginates Chondron Guar gum Pectin Carbopol Polyox Colloidal silicon dioxide NATURAL INORGANICS SEMISYNTHETICS Gelatin Casein Wool fat Egg yolk Bentonite Attapulgite Veegum Colloidal alumina Milk of magnesia Magnesium oxide Magnesium trisilicate Methylcellulose Carboxy methylcellulose Hydroxy methylcellulose Microcrystalline cellulose

34. Hydrocolloids Thickening, gelling and stabilizing agents. Water-soluble polysaccharides. Amount required is very low. Also interact with proteins, allowing for protein stabilization and protection applications. PH 201. 4434 TYPES OF EMULGENTS Natural – Plant source (always forms o/w emulsions)

35. Gum acacia Solubility: Cold water soluble pH ~4.0 - 4.8 Constituents: Anionic exudate polysaccharide of calcium salt of arabic acid, along with magnesium and potassium. Major monosaccharides: D-galactose, D-glucuronic acid; Used as powder, 35% mucilage or as 10% syrup Low viscosity Milk reactivity Newtonian flow Excellent emulsifier Foam stabilizer Adhesive Film-foaming PH 201. 4435 Natural – Plant source

36. Tragacanth Astralgus gummifer is a plant exudate from a shrub originally located in the Middle East. Two components: water-swellable [bassorin] water-soluble [tragacanthin] Others Acid stable and resistant Bifunctional emulsifier Creamy texture Pseudoplastic Film former Bodying agent Adhesive Suspending agent Thickener pH 5.0-6.0 PH 201. 4436 Natural – Plant source

37. Alginate Polysaccharide produced from brown seaweed. Brown seaweed contains mixed alginic acid salts, which are the basic raw materials used in the production of alginates. The seaweed grows mainly in the inter-tidal zones of cold waters in many countries throughout the world. PH 201. 4437 Natural – Plant source

38. Guar gum From the seeds of (Leguminosa: Cyamopsis tetragonolobus), The hull and germ of the seed are separated from the endosperm by a natural milling process. Galactomannan consisting of a mannose chain branched with galactose units. High water-binding capacity - extremely high viscosity in water-based systems even at low dosage levels. Mainly used as a thickening agent. Stable at pH values between 3 and 11 - Used in a wide range of products. cold soluble. synergism with xanthan gum. PH 201. 44 38 Natural – Plant source

39. Pectin The word “pectin” stems from the Greek word “pektos”, which means firm and hard. Commercial pectin is derived from the peel of citrus fruits (lemon, lime and orange) or from apple pomace. PH 201. 4439 Natural – Plant source

40. Agar Composition: Sulfated galactose monomers D-galactose, 3,6-anhydro-L- galactose linear polymer of sulfated D- glucuronic acid and Agarose (a neutral polymer of agarobiose) Agarose-beta-D-gal; 3 anhydro-alpha-L-gal D-glcA=D-glucuronic acid D-galA=D-galacturonic acid L-gulA=L-guluronic acid PH 201. 44 40 Natural – Plant source Polysaccharide found in the cell walls of some red algae

41. Animal source Egg yolk Contains lecithin & Cholesterol Produces o/w emulsions Gelatin Animal protein – o/w emulsion – requires preservative. Incompatible with negatively charged hydrocolloids such as acacia, tragacanth or agar. Available in two forms Pharmagel A (Acid treated) – Isoelectric point 7 - 9. Pharmagel B – Alkali treated – Isoelectric point 4.7 - 5. Wool fat Contains cholesterol and its esters. W/o emulsions – ointments & Creams. PH 201. 4441

42. Mineral source Bentonite Only official clay Colloidal aluminium silicate Non toxic, not absorbed from GIT Two types – Calcium bentonite & Sodium bentonite Bentonite magma (5%) give either o/w or w/o emulsions depending on the order of mixing. PH 201. 4442

43. Mineral source Others Pulgite Veegum Colloidal alumina Magnesium oxide Magnesium trisilicate Milk of Magnesia PH 201. 4443

44. Semi synthetic hydrocolloids Methylcellulose Soluble in cold water Insoluble in hot water Non ionic Stable over wide range of PH Non toxic Carboxy methylcellulose Available in low, medium and high viscosity grades Hydroxy ethylcellulose Un affected by PH from 4 -10. Microcrystalline cellulose PH 201. 4444

45. Synthetic Hydrocolloids Carbopol Carbopol 934, 940 & 941. More compatible Suitable for both internal & external preparations Polyox Polymerized product of Ethylene oxide MW in millions Coagulated by electrolytes and temperature PH 201. 4445

46. Surface active agents The term surfactant is a blend of "surface acting agent". Surfactants are usually organic compounds that are amphipathic, meaning they contain both hydrophobic groups (their "tails") and hydrophilic groups (their "heads"). They are soluble in both organic solvents and water. Surfactants constitute the most important group of detergent components. PH 201. 4546

47. Uses of Surfactants 1. Emulsifiers Water in Oil - Low HLB Oil in Water - High HLB 2. Foam Stabilizers 3. Lipid Crystal Modifiers 4. Wetting Agents 5. Solubilizers 6. Starch Complexers 7. Protein Modifiers 8. Detergents PH 201. 4547

48. PH 201. 4548 Alkali soaps Metallic soaps Amine soaps Sulphated oils Sulphated alcohols Aliphatic sulphonates Aromatic sulphonates Quarternary ammonium compounds Eg. Benzalkonium chloride Esters Glyceryl monostearate Sorbitan esters Ethers Brij Octoxynol Tyloxynol Ethers Esters Tweens Spans AnionicsCationicsNonionicAmpholytics Surfactants Meranols Deriphates

49. PH 201. 4549 A micelle - the lipophilic ends of the surfactant molecules dissolve in the oil, while the hydrophilic charged ends remain outside, shielding the rest of the hydrophobic micelle

50. Critical micelle concentration (CMC) All surfactants possess the common property of lowering surface tension when added to water in small amounts. The characteristic discontinuity in the plots of surface tension against surfactant concentration can be experimentally determined. The corresponding surfactant concentration at this discontinuity corresponds to the critical micelle concentration PH 201. 4550

51. How do surfactants work? Types of emulsion PH 201. 4551

52. How do surfactants work? SINGLE SURFACTANT Cetrimide Repulsion Less stable film MIXED SURFACTANT Cetyl alcohol Cetrimide More stable condensed film (barrier) Charge repulsion between drops PH 201. 4552 + + + + + + ++ + + + + + + ++ + + + + + ++ + + + + + + ++ + + + + OIL WATER

53. Good emulgent? Poorly soluble in both phases Concentrates at the interface Relative attraction for the two phases > 90° produces o/w < 90° produces w/o Equals 90° ? Depends on oil : water ratio PH 201. 4553 Poor emulgent Contact angles

54. Anionics An anionic surface-active agent is the reaction product of an organic compound such as a high molecular weight acid or alcohol with an inorganic compound such as sodium hydroxide or sulfuric acid, yielding a product wherein the organic part of the molecule, or the water-insoluble part of the molecule, has a negative charge and the water-soluble part of the molecule wherein the sodium ion has a positive charge. The anionics have the advantage of being high and stable foaming agents. PH 201. 45 54

55. Cationics Cationics are formed in reactions where alkyl halides react with primary, secondary, or tertiary fatty amines. Here the water-insoluble part of the molecule has a positive charge and the water-soluble part of the molecule is negatively charged. Have no detergent action when formulated into an alkaline solution. PH 201. 4555

56. Nonionic Nonionic surface-active agents have a hydrophobic/hydrophilic balance wherein there is neither a negative nor a positive charge in either part of the molecule, thus giving it the nonionic terminology. These surface-active agents have the advantage that they are not affected by water hardness or pH changes as the anionic and cationic surfactants are, and in many cases it is an advantage that they are considered medium to low foaming agents. PH 201. 4556

57. Surfactants – Affirmed GRAS Emulsifiers Diacetyl tartaric acid esters of mono- and diglycerides. Glyceryl monooleate. Glyceryl monostearate. Glyceryl behenate. Lecithin Mono- and diglycerides. Monosodium phosphate derivatives of mono- and diglycerides PH 201. 4557

58. Mono & diglycerides Most commonly used Generally as mono & di HLB values range from 1 to 10 Produced by transesterification of glycerol and triacylcerides PH 201. 4558

59. Polysorbates Polyoxyenthyene esters of sorbitan monoesters Polysorbate 60 Polyoxyethylene sorbitan monostearate or Tween 60 - HLB = 14.9 Polysorbate 65 Polyoxyethylene sorbitan tristearate Polysorbate 80 Polyoxyethylene sorbitan tristearate Special dietetic foods, fat soluble vitamins PH 201. 4559

60. Sorbitan monostearate Sorbitan monostearate approved for food use HLB = 4.7 Used in conjunction with polysorbates PH 201. 4560

61. Lecithin A mixture of phospholipids including phosphatidyl cholines, phosphatidyl ethanolamines, inositol phosphatides, etc Can be chemically modified by provide a wide range of HLB values for various applications PH 201. 4561

62. Hydrophillic - Lipophillic Balance (HLB) This is a concept for choosing emulsifiers. The value of HLB ranges from 1-20. Low HLB emulsifiers are soluble in oil while high HLB emulsifiers are soluble in water.. PH 201. 4562

63. HLB…. The HLB of a surfactant is a measure of the degree to which it is hydrophilic or lipophilic, determined by calculating values for the different regions of the molecule, as described by Griffin. Other methods - by Davies. PH 201. 4563

64. Griffin's method Griffin's method for non-ionic surfactants as described in 1954 works as follows: HLB = 20 * Mh / M Where Mh is the molecular mass of the hydrophilic portion of the Molecule, and M is the molecular mass of the whole molecule, giving a result on an arbitrary scale of 0 to 20. PH 201. 4564

65. How to calculate HLB value? For alkanoic (fatty) acid esters of polyhydric alkanols HLB = (1-S/A) where S is the saponification number and A is the acid number of the fatty acid For non-ionic surfactants with polyoxyethylene as the only hydrophilic component HLB = E/5 where E is the percentage w/w of PEG (polyoxyethylene) PH 201. 4565

66. Griffin's method… The HLB value can be used to predict the surfactant properties of a molecule: 1 to 3.5 Antifoaming agents 3.5 to 6 W/O emulsifiers 7 to 9 Wetting and spreading agents 8 to 12 O/W emulsifiers 12 to 15 Detergents 15 to 20 Solubulizers or Hydrotropes. PH 201. 4566

67. Solubility and HLB Solubility HLB Range No dispersability in water 1 - 4 Poor Dispersion in water 3 - 6 Milky appearance 6 - 8 Stable milky appearance 8 - 10 Translucent to clear dispersion 10 - 13 Clear solution 13 + PH 201. 4567

68. Surfactant HLB Sorbitan trioleate (Span 85) 1.8 Sorbitan tristearate (Span 65) 2.1 Sorbitan sesquioleate (Arlacel 83) 3.7 Glyceryl monostearate, NF 3.8 Sorbitan monooleate, NF, (Span 80) 4.3 Sorbitan monostearate, NF, (Span 60) 4.7 Sorbitan monopalmitate, NF, (Span 40) 6.7 Sorbitan monolaurate, NF, (Span 20) 8.6 PH 201. 4568

69. PH 201. 4569 Polyoxyethylene sorbitan tristearate, (Tween 65) 10.5 Polyoxyethylene sorbitan trioleate, (Tween 85) 11.0 Polyethylene glycol 400 monostearate 11.6 Polysorbate 60, NF, (Tween 60) 14.9 Polyoxyethylene monostearate (Myrj 49) 15.0 Polysorbate 80, NF, (Tween 80) 15.0 Polysorbate 40, NF, (Tween 40) 15.6 Polysorbate 20, NF, (Tween 20) 16.7

70. Ingredient "Required HLB" for w/o o/w Emulsion Acid, Stearic 6 15 Alcohol, Cetyl -- 15 Alcohol, Stearyl -- 14 Lanolin, Anhydrous 8 10 Oil, Cottonseed 5 10 Oil, Mineral 5 12 Petrolatum 5 12 Beeswax 4 12 PH 201. 4570

71. Emulsification Comminution (Destruction) Mechanical energy or pressure is doing the job the most widely used procedure Condensation (Construction) Thermodynamics takes care swelling of colloidal systems such as micelles or solid (polymer) particles with liquids PH - 201 - 4671

72. Methods for preparing Emulsions for Internal use The methods commonly used to prepare emulsions can be divided into two categories: Trituration Methods Dry Gum Method Wet Gum Method Bottle Method PH - 201 - 4672

73. PH - 201 - 4673 Comminution methods

74. Comminution - Structure of the Emulsion Which liquid forms the dispersed phase and which will be the continuous one? Influenced by Volume ratio Kind of the emulsifying agent Concentration Shear exceeds the cohesive forces of the liquids in the drops they split up to smaller units Cleavage occurs as long as a balance between the external stress and the internal stress is reached PH - 201 - 4674

75. Comminution power Duration of the comminution Viscosity of both phases Interfacial tension Degradation after comminution is stopped PH - 201 - 4675 Emulsion preparation by Comminution is influenced by:

76. Acacia emulsions Emulsions for internal use at dispensing table. Primary emulsion is to be prepared first. Primary emulsion is the initial thick emulsion during which globules of internal phase is reduced to the minimum size. The quantities of oil, water and gum for primary emulsion depends on the type of oil used. The primary emulsion can be diluted with any volume of water. Two methods – Dry gum method Wet gum method can be used for the preparation of primary emulsion PH - 201 - 4676

77. Table 46.1 : Parts of Oil : Water : Gum, for primary emulsion Type of oilExampleQuantities for primary emulsion OilwaterGum Fixed Almond oil Arachis oil Castor oil Cod liver oil 421 Mineral Liquid paraffin 321 Volatile Turpentine oil Cinnamon oil Peppermint oil 221 Oleo-resin Male fern extract 121 PH - 201 - 4677

78. Continental or Dry Gum Method Also called as "4:2:1" Method 4 parts (volumes) of oil 2 parts of water 1 part of gum used in the preparation of primary emulsion Acacia or other o/w emulsifier is triturated with oil in a perfectly dry Wedgwood or porcelain mortar until thoroughly mixed. PH - 201 - 4678

79. PH - 201 - 4679 After the oil and gum have been mixed, the two parts of water are then added all at once and the mixture is triturated vigorously. The finer the globules, the whiter is the product.

80. Dry gum method…. Do not use glass mortar: Too smooth a surface to produce the proper size reduction of the internal phase. Always use dry measures to measure oil Pestle and mortar must be absolutely dried Quantities of oil, water and gum should be measured/weighed accurately PH - 201 - 4680

81. PH - 201 - 4681 Trituration must be vigorous, continuous and unidirectional after the addition of water until the primary emulsion is formed (hearing of clicking sound). Dilute primary emulsion with more water in small additions

82. Olive oil 30 mL Purified water upto 120 mL Formula for primary emulsion Olive oil 30 mL Water 15 mL Gum acacia 7.5 g Method: Measure the oil in a dry measure. Powder gum acacia in a dry mortar. Add oil and mix thoroughly. Water is added all at once and Triturate unidirectionally, vigorously and continuous until clicking sound is heard. (Formation of primary emulsion) PH - 201 - 4682 Emulsions prepared by dry gum method… R

83. PH - 201 - 4683 Add more quantity of water until it become pourable. Remove any foreign particles if present. Transfer to the tared final container. Add rinsing too. Incorporate more water to produce the final volume. Shake well. Cork, label and dispense.

84. English or Wet Gum Method Is not popular because the results are not good. Same proportion of oil, water and gum are used as in the continental or dry gum method but the order of mixing is different. Mucilage of the gum is prepared by triturating acacia (or other emulsifier) with water. The oil is then added slowly in portions, and the mixture is triturated to emulsify the oil. PH - 201 - 4684

85. Special cases 1. Inorganic salts: Dissolved in part of vehicle and diluted before adding to the diluted emulsion in small amounts with constant stirring. High concentrations of electrolytes may precipitate the emulsifying agent. PH - 201 - 4685

86. PH - 201 - 4686 2. Tinctures and other Alcoholic solutions: The emulsion is diluted to its final volume less the volume of the alcoholic solution. The latter is added drop by drop to the centre of the emulsion with constant stirring.

87. Special cases…. 3. Substances insoluble in oil or water: Such substances are finely powdered and gradually triturated with diluted emulsion, or they can be mixed with acacia powder before preparing emulsion. PH - 201 - 4687

88. PH - 201 - 4688 4. Modification when preparation of oil is small: In case of acacia emulsion, if oil phase is less than 20%, istarts creaming readily. Thus to prevent this a bland fixed oil (e.g. Arachis oil) should be added to increase the oil phase upto 20% of the total volume e.g. emulsion of calciferol and Bromoform.

89. Official preparations Castor oil Emulsion Castor oil30ml Mucilage of Acacia60ml Chloroform water to 180ml Comments: It is a o/w type of emulsion prepared by emulsification with mucilage of acacia (40% acacia in chloroform water). It is internally taken for its purgative action. Method: Use the wet-gum method for acacia emulsion. PH - 201 - 4689

90. Bottle or Forbes Bottle Method Useful for extemporaneous preparation of emulsion from volatile oils or oleaginous substance of low viscosity. Put powdered acacia in a dry bottle Add 2 parts of oil Thoroughly shake the mixture in the capped bottle. PH - 201 - 4690

91. PH - 201 - 4691 A volume of water approximately equal to the oil is then added in portions, the mixture being thoroughly shaken after each addition. This method is not suitable for viscous oils (i.e. high viscosity oil).

92. Emulsions for External use Soap emulsions e.g. soft soap is used as an emulsifying agent. If the quantity of soap is not mentioned in the preparation, the following proportions: For fixed and Volatile oils : 10 percent of the weight of oil. For Fats : 20 percent of the weight of oil PH - 201 - 4692

93. Emulsions for External use Method : Finely powder any solid ingredients and mix it with soap in a mortar. Add oil in small amount, mix well after each addition. Transfer the above mixture in a beaker. Take a calibrated bottle about 50% larger than the final volume of product, in which water is added. Add the oily mixture from the beaker into bottle is small quantites, shaking vigorously after each addition Add any other fluid liquid and makeup the volume. If necessary, pass it through a muslin strainer Finally, transfer gently to a container of the correct size PH - 201 - 4693

94. Official preparation Turpentine Liniment B.P. Soft soap75g Camphor50g Turpentine oil650ml Purified water225ml Comments: It is an emulsion-type liniment made with an alkali soap. It is used as counter-irritant. Method: Follow the general method of preparation of soap emulsions. PH - 201 - 4694

95. Ammonium soap type Ammonium soap is prepared by interaction of a fatty acid and ammonia during the preparation. White Liniment B.P.C. Ammonium Chloride12.5g Dilute ammonia solution45.0ml Oleic Acid83.3ml Turpentine oil250.0ml Purified water625.0ml PH - 201 - 4695

96. Method: Mix the turpentine oil and oleic acid in a bottle 50% larger than the prescribed volume. Add an equal volume of warm water (approx. 50°C) to the dilute ammonia solution and add this diluted ammonia solution, in small amounts, to the oily liquid, shaking vigorously after each addition. PH - 201 - 4696

97. PH - 201 - 4697 Dissolve the ammonium chloride in the rest of the water and add to the bottle, in small amounts, again shake vigorously after each addition. Transfer to calibrated bottle and finally make-up the volume

98. ‘Lime’ Cream type Lime creams are w/o type of emulsions. E.g. Olive oil contains sufficient free fatty acids which can combine with lime water producing enough calcium soap to emulsify rest of the oil. Calamine1g Zinc Oxide1g Olive oil15ml Lime water15ml PH - 201 - 4698

99. PH - 201 - 4699 Method: Sift suitable quantities of the powders. Weigh out the required amount and mix in a mortar. Use a separate sieve for each powder. Use olive oil to produce a smooth paste, add the lime water (freshly prepared) and triturate briskly to produce a good emulsion.

100. Instabilities in Emulsions An emulsion is a thermodynamically unstable preparation. So care has to be taken that the chemical as well as the physical stability throughout the shelf life. There should be no appreciable change in Mean particle size or Size distribution of the droplets of the dispersed phase and Secondly droplets of the dispersed phase should remain uniformly distributed throughout the system. PH - 201 - 47100

101. Instabilities seen in emulsion can be grouped as PH - 201 - 47101

102. Instabilities seen in emulsion can be grouped as PH - 201 - 47102

103. Instabilities of emulsions PH - 201 - 47103 Stable Creaming/ Aggregation Coalescence Cracking emulsion Sedimentation Degree of severity

104. 1) Creaming or Sedimentation An emulsion is said to cream when the oil or fat rises up to the surface (Creaming) or settles at the bottom (Sedimentation), but remains in the form of globules, which may be redistributed throughout the dispersion medium by shaking. An oil of low viscosity tends to cream more readily than one of high viscosity. PH - 201 - 47104

105. PH - 201 - 47105 Increasing the viscosity of the medium decreases the tendency to cream. It is a reversible phenomenon which can be corrected by mild shaking.

106. Stokes' Law The factors affecting creaming are best described by stroke’s law V= 2r 2 (d 1 -d 2 ) g/9η Where V = rate of creaming r =radius of globules d 1 = density of dispersed phase d 2 = density of dispersion medium g = gravitational constant η = viscosity of the dispersion medium PH - 201 - 47106

107. Stokes' Law Creaming or sedimentation is Directly proportional to: 1. Diameter of the particle squared 2. Difference in density between the particle and the continuous phase and Inversely proportional to 3. Viscosity of the continuous phase PH - 201 - 47107

108. Approaches to decrease creaming Reduction of globule size: Bigger is the size of the globules, more will be the creaming. Gglobule size should be reduced by homogenization. PH - 201 - 47108

109. PH - 201 - 47109 Increasing the viscosity of the continuous phase: More the viscosity of the continuous phase, less will the problem of creaming. The viscosity of the continuous phase should be increased by adding suitable viscosity enhancers like gum acacia, tragacanth etc.

110. 2) Aggregation and Coalescence or Cracking The aggregation and possible coalescence of the dispersed droplets to reform separate bulk phases. These are more serious problems than creaming. In aggregation the dispersed droplets come together but do not fuse. It is not as serious as coalescence. It is somewhat reversible and upon shaking may form emulsion. It is related to electrical potential on the droplet PH - 201 - 47110

111. PH - 201 - 47111 In coalescence The complete fusion of droplets and ultimate separation of the two immiscible phases. It depends on the structural properties of the interfacial film (Emulgent). Leads to breaking of emulsion and will not restore upon shaking.

112. Insufficiency of emulgent Decomposition of emulgent Addition of substance incompatible with emulgent. Alteration of PH of the continuous phase. Presence of electrolyte Presence of antagonistic emulgent Eg. Addition of Calcium oleate to an O/W Emulsion prepared by using Sodium oleate Abrupt changes in temperature Microbial growth Addition of common solvent like alcohol Eg. Turpentine Oil, Soft soap, Water PH - 201 - 47112 Reasons for cracking

113. PH - 201 - 47 113 Presence of antagonistic emulgent Eg. Addition of Calcium oleate to an O/W Emulsion prepared by using Sodium oleate Abrupt changes in temperature Microbial growth Addition of common solvent like alcohol Eg. Turpentine Oil, Soft soap, Water

114. Salt (NaCl) Effect on the Emulsion Stability (2 day test) PH - 201 - 47114 Amount of Sodium chloride solution 20 ml 5 ml 2 ml 1 ml 0.5 ml 0.25 ml

115. PH - 201 - 47115 Effect of Temperature in Oven (130 o F)At room temperature

116. 3) Phase Inversion In phase inversion o/w type emulsion changes into w/o type and vice versa. It is a physical instability. It may be brought about by the addition of an electrolyte or by changing the phase volume ratio or by temperature changes. PH - 201 - 47116

117. PH - 201 - 47117 Phase inversion can be minimized by using the proper emulsifying agent in adequate concentration, keeping the concentration of dispersed phase between 30 to 60 % and by storing the emulsion in a cool place.

118. Packaging of Emulsions Depending on the use, emulsions should be packed in suitable containers. Emulsions meant for oral use are usually packed in well filled bottles having an air tight closure. Light sensitive products are packed in amber coloured bottles. For viscous emulsions, wide mouth bottles should be used. PH - 201 - 47118

119. Labelling of Emulsions The label on the emulsion should mention that these products have to be shaken thoroughly before use. External use products should clearly mention on their label that they are meant for external use only. PH - 201 - 47119

120. Storage of Emulsions Emulsions should be stored in a cool place Refrigeration should be avoided as this low temperature can adversely effect the stability of preparation. PH - 201 - 47120

121. Microorganisms can proliferate easily in emulsified systems with high water content, particularly if carbohydrates, proteins or steroidal materials are also present. PH - 201 - 47121 Preservation from microorganisms

122. PH - 201 - 47122 Contamination due to microorganisms can result in problems such as color and odor change, gas production, hydrolysis, pH change and eventually breaking of emulsion. Emulsified systems be adequately preserved.

123. An ideal preservative should be Nonirritant Nonsensitizing Nontoxic in the concentration used Physically as well as chemically compatible with other ingredients of the emulsions and with the proposed container of the product Stable and effective over a wide range of pH and temperature PH - 201 - 47123

124. PH - 201 - 47124 Have a wide spectrum of activity against a range of bacteria, yeasts and moulds. Have high water solubility and a low oil/water partition coefficient Bactericidal rather than bacteriostatic activity It should not impart any taste, color or odor to the product

125. Examples of antimicrobial preservatives Parahydroxybenzoate esters Methyl, Propyl and Butyl parabens Organic acids Ascorbic acid and Benzoic acid Organic mercurials Phenylmercuric acetate and phenylmercuric nitrate Quarternary ammonium compounds Cetrimide Cresol derivatives Chlorocresol Miscellaneous agents Sodium benzoate, chloroform and phenoxyethanol. PH - 201 - 47125

126. Preservation from oxidation Oxidative changes such as rancidity and spoilage due to atmospheric oxygen and effects of enzymes produced by micro-organisms is seen in many emulsions containing vegetables and mineral oils and animal fats. Antioxidants can be used to prevent the changes occurring due to atmospheric oxygen. PH - 201 - 47126

127. The ideal antioxidant should be Nontoxic Nonirritant Effective at low concentration under the expected conditions of storage and use Soluble in the medium Stable For oral preparations - also be odorless and tasteless. PH - 201 - 47127

128. Commonly used antioxidants Alkyl gallate such as ethyl, propyl or dodecyl gallate Butylated hydroxyanisole (BHA) Butylated hydroxytoluene (BHT) PH - 201 - 47128