Emulsions and Semisolids PDF

Emulsions and Semisolids September 28, 2023 Additional Reading • Martin’s Physical Pharmacy – PDF upload of Chapter 17: Coarse Dispersions Emulsions Emulsions • Thermodynamically unstable system consisting of at least two immiscible liquid phases, one of which is dispersed as globules (dispers...

Emulsions and Semisolids September 28, 2023 Additional Reading • Martin’s Physical Pharmacy – PDF upload of Chapter 17: Coarse Dispersions Emulsions Emulsions • Thermodynamically unstable system consisting of at least two immiscible liquid phases, one of which is dispersed as globules (dispersed phase) in the other liquid phase (continuous phase) • Stabilized by the presence of an emulsifying agent to prevent coalescence of globules (dispersed phase). • Oil-in-water (o/w) OR water-in-oil (w/o) • Consistency of the liquid (continuous phase) or globules can range from a liquid to a semisolid (aka, from lotions of low viscosity to thicker ointments and creams) 3 Applications of Emulsions: Oral formulation of medicinal emulsions 1. To mask the taste. Usually of the o/w type and require the use of an o/w emulsifying agent (E.g., nonionic surface-active agents, acacia, tragacanth, gelatin) 2. Enhance bioavailability (E.g., oil soluble vitamins are absorbed more completely as an emulsion) 3. Parenteral delivery of oil-soluble drugs (E.g., Taxol) as O/W emulsion Topical formulation 1. Can be O/W or W/O (e.g. for O/W, requires use of emulsifying agents such as SDS, sodium oleate, trethanolamine stearate) 2. O/W emulsions can be easily removed from the skin with water, eliminates oiliness and staining 3. W/O emulsions can be applied more evenly due to skin sebum being more wetted by oil than water, more softening to skin since resists drying and removal upon contact with water 4 Emulsions: How Can You Tell if Its O/W or W/O? Using the naked eye, it is difficult to differentiate between o/w or w/o 5 1. Dye solubility test A water-soluble dye (methylene blue or brilliant blue FCF) can be dusted on top of the emulsion a) O/W: dye dissolves and diffuses throughout the emulsion b) W/O: dye will stick in clumps on the surface Oil - soluble dye (e.g. red) W/O Water -soluble dye (e.g. blue) O/W O/W W/O 6 2. Conductivity test Water is a good conductor of electricity whereas oil is a nonconductor. Electrodes are submerged in the emulsion and connected to an external electrical source a) O/W: will carry a current (water as continuous phase) b) W/O: will not carry a current (oil as continuous phase) = Bulb glows with O/W = Bulb doesn’t glow with W/O 7 3. Dilution test a) O/W: emulsion can be diluted with water b) W/O: emulsion can be diluted with oil Few drops of water Water distribute uniformly Few drops of emulsion Water separate out as layer O/W emulsion W/O emulsion 8 Theory of Emulsification Oil Agitation Water W= γ ο/ω. Surface free energy Oil Water Water Separate rapidly into two clear defined layers A Interfacial tension Oil Surface area Formation of small droplets System is thermodynamically unstable and “highly energetic” Surface area Interfacial tension • System tends to separate in two layers to reduce the surface area • To prevent coalescence and separation, emulsifying agents must be used (helps decrease the interfacial tension hence surface free energy) 9 Instability of Emulsions 10 Types of Emulsifying Agents Must be present at the interface to prevent coalescence of the internal phase: 1. Surface active agents or SAA: adsorb at the oil/water interface to form a monomolecular film to reduce the interfacial tension 2. Hydrophilic colloids: form a multi-molecular film around the dispersed droplet. Does not appreciably lower the interfacial tension (in contrast to SAA) 3. Finely divided solid particles: adsorb at the interface between two immiscible liquid phases to form a particulate film 11 Surface Active Agents (SAA) 12 SAA - O/W emulsifying agents • Helps reduce the interfacial tension • Forms a monolayer at the oil-water interface to prevent coalescence • provides surface charge leading to repulsion between globules (electrostatic repulsion) • Hydrophilic barrier also works in o/w for physically preventing globule coalescence (steric hindrance) 13 SAA - W/O emulsifying agents • Same general functions as before but… • Hydrophobic barrier is better in w/o for physically preventing droplet coalescence Examples: water alkyl chains (fatty acid) 14 HLB: an arbitrary scale of values to serve as a measure of the hydrophilic-lipophilic balance of surfactants  Surfactants  Surface active agents  Amphiphiles Generally, • More polar, higher HLB favors O/W emulsions • Less polar, lower HLB favors W/O emulsions w/o emulsifying agents 15 Antifoaming Pharmaceuticals • Simethicone is the active ingredient in Maalox, Mylanta, and Gas-X to relieve bloating • Sources of gas – carbonated drinks, swallowed air or produced by bacteria in the intestines (E.g. colon) • Simethicone reduces the surface tension of gas bubbles which prevents bubble formation 16 Head-to-Head Comparison SAA classification: • Anionic SAA are mainly used in external applications • Cationic SAA are also externally used; possess good antimicrobial activity (E.g., benzalkonium chloride) • Nonionic SAA are stable over a wide range of pH and electrolyte conc; less toxic, reduces coalescence via steric hindrance. oleic acid (HLB 1) polyethylene lauryl ether (HLB 9.5) sodium dodecyl sulfate (HLB 40) 17 18 In practice: • A combination of emulsifiers is used • A mostly hydrophilic emulsifying agent is needed for the aqueous phase, and a mostly hydrophobic emulsifying agent is needed for the oil phase. • The combination of SAA leads to formation of a closely packed and condensed film (a complex film) at the interface that produces an excellent emulsion • The resulting complex film should ideally be flexible so that it is capable of reforming rapidly if broken or disturbed 19 • Hydrophilic Tween 40 is mixed with a lipophilic (hydrophobic) Span 80 and used for an o/w emulsion (see diagram) • Hydrocarbon portion of Span lies in the oil globule and sorbitan portion lies in the aqueous phase. Bulky sorbitan heads prevent the hydrocarbon tails from close association in the oil. Close Packing is Important • When Tween 40 is added, part of its hydrocarbon tail is in the oil phase, and the rest of the molecule is in the aqueous phase. Within the oil phase, the orientation of the Tween and Span results in effective van der Waals interactions (aka flexibility). The film is strengthened, and the stability of the o/w emulsion prevents particle coalescence. • The emulsion type formed using surfactants depends on the HLB; should result in close packing at the interface (condensed film). • In general, o/w emulsions are formed with surfactants of HLB = 9-12; w/o emulsions are formed with surfactants of HLB = 3-6. 20 • Example Rx  Mineral oil 8g  SAA (Span 80 + Tween 80) 2g  Purified water 100 mL  The required HLB for the mineral oil is 10.5, HLB of Span 80 = 4.3 and the HLB of Tween 80 = 15 • How much Span 80 and Tween 80 are required to produce a stable o/w emulsion? • Fs*HLBS + FT*HLBT = required HLB of the oil If fraction of Span = X, therefore the fraction of Tween = 1 – X X*4.3 + (1-X)*15 = 10.5, or 10.7X = 10.5 X=0.42 for fraction of Span, amount of Span = 2*0.42 = 0.84 g 1-X = 1 - 0.42 = 0.58, amount of Tween = 2*0.58 = 1.16 g 21 Hydrophilic Colloids • Form a multi-molecular film • Do not cause an appreciable lowering of interfacial tension. Their action is due to the fact that multimolecular films are strong and resist coalescence. • Can affect rheology properties of the final product by increasing viscosity of dispersion medium • Size of the particles is very important; larger particles can lead to coalescence! • Typically used in o/w emulsions • Examples – acacia gum, methylcellulose, and proteins (gelatin and albumin) acacia methylcellulose 22 Finely Divided Solid Particles • Form a particulate film • Finely divided solids that are wetted to some degree by both oil and water; concentrate at the interface  Finely divided solids that are wetted preferentially by water form o/w emulsions; those that are wetted better by oil form w/o emulsions. • Examples - Bentonite, hectorite, kaolin, magnesium aluminum silicate, montmorillonite, aluminum hydroxide, magnesium hydroxide, silica https://www.europeancoatings.com/articles/archiv/silica-nanoparticlesstabilise-emulsions-in-a-new-way 23 Physical Stability of Emulsions Stability of an emulsion is generally characterized by:  Absence of creaming  Absence of coalescence of the internal phase  Maintenance of elegance with respect to appearance, odor, color, etc.  Absence of phase inversion (e.g. emulsion changes from o/w to w/o) 24 Stokes’ Law for Emulsions and Creaming Phenomena • “Sign” of sedimentation rate is negative in creaming • Creaming occurs if density of the globule < density of dispersion medium • Larger oil globules and the less viscous the external phase, the greater is the creaming rate  Can reduce creaming by increasing the viscosity of the medium (by adding thickening agents such as methylcellulose, tragacanth, etc.)  Can reduce creaming by decreasing particle size. Particles smaller than 2-5 µm can undergo Brownian motion so particles settle or cream slower than predicted by Stokes’ Law. • Creaming is a reversible process, but coalescence is an irreversible process 25 Coalescence and Breaking of the Internal Phase • Separation of the internal phase from the external phase is called breaking of the emulsion.  When breaking occurs, simple mixing fails to re-suspend the globules in a stable emulsified form, since the film surrounding the particles has been destroyed and the oil globules tend to coalesce. Breaking is irreversible. • Particle size does not correlate well with increased/decreased breaking, nor does viscosity. • Phase-volume ratio (relative volumes of oil and water in an emulsion) contributes to stability (prevention of breaking) of an emulsion. If you try to incorporate greater than around 74% of oil in an o/w emulsion, the oil globules often coalesce and breaking occurs. • Generally, a phase-volume ratio of 50:50 results in the most stable emulsion. 26 Preservation of Emulsions • Parenteral emulsions - must be sterile • Oral emulsions - sterile conditions not always necessary • Growth of microorganisms can cause:  Physical phase separation  Discoloration  Gas/odor formation  Changes in rheologic properties • Preservatives - Bacteria tend to grow in the aqueous phase of an emulsified system so preservative selected must partition into the water phase. • Additionally, the preservative must be in the free, unbound, unionized form to penetrate the membrane of the bacteria. 27 Semisolids for Topical Applications • Semisolids can be classified as gels (e.g. hydrogels) and emulsion-type semisolids • Common dosage forms:  Gels O/W emulsion W/O emulsion  Ointments • For insoluble drug • For water soluble drug • For local effect • Can be used to hydrate the  Creams • Easy to wash from skin • No greasy texture of oily preparation • Acceptable by consumer upper layer of the epidermis • Can help increase absorption of topical drugs • Can be used to clean skin from dirt • Not acceptable by consumer 28 Gels • Gels are useful as liquid formulations in oral, topical, vaginal, and rectal administration. • A gel is a semisolid system of at least 2 components, consisting of a condensed mass enclosing and interpenetrated by liquid. • Gels can be clear formulations when all of the particles completely dissolve in the dispersing medium. But this doesn't occur in all gels, and some are turbid. • Gels are made using substances (called gelling agents) that undergo a high degree of cross-linking or association when hydrated and dispersed in the dispersing medium 29 One- and Two- Phase Gel Systems • If the gel contains small discrete particles, the gel is called a twophase system. If the gel does not appear to have discrete particles, it is called as a one-phase system.  Two-phase gel consist of floccules of particles (weak van der Waals interactions) (a, b)  One-phase gel is governed by stronger van der Waals forces between macromolecules (c, d); no definite boundaries exist between the dispersed macromolecules and the liquid. Flocculated particles Matted fibers (eg. soap gels) Network of elongated particles or rods Crystalline and amorphous regions (eg. gel of carboxymethycellulose) 30 Syneresis and Gel Swelling • Syneresis = shrinking  Syneresis occurs when a gel stands for some time; it often shrinks naturally (contracts), and some of its liquid gets pressed out (observed in food jellies and gelatin desserts).  Bleeding is the liberation of oil or water from ointment bases, results from a deficient gel structure rather than from the contraction involved in syneresis • Swelling = enlarging  Swelling is the taking up of liquid by a gel with an increase in volume (opposite of syneresis). Only those liquids that solvate a gel can bring about swelling.  Inhibition is defined as when gels take up a certain volume of liquid without a measurable increase in volume. 31 Drug Diffusivity (D) in the Gel 1  ln D = ln D0 − K f  −1 H  • Do = diffusivity of solute in water (cm2/sec) • Kf = constant (cm2/sec) • H = matrix hydration (unitless) eq. swollen gel wt. - dry gel wt. H = eq. swollen gel wt. 32 Example Calculate the diffusion coefficients of Drug A in a gel for 2 gel hydrations, H = 0.4 and H = 0.9. Diffusion coefficient of Drug A in water = D0 = 1.82 x 10-6 cm2/sec, Kf = 2.354 For H = 0.4 For H = 0.9 1  ln D = ln D0 − K f  −1 H  2   cm 2  1 −6 cm ln D = ln1.82 ×10 −1   = 2.354 sec  0.4  sec   = −13.2167 − 3.531 = −16.7477 2 cm D = e−16.7477 = 5.33 ×10−8 sec 2 −6 cm −13.478 D=e = 1.4 ×10 sec This example shows that gel swelling (hydration) favors drug release, since diffusivity of the drug is increased. 33 Ointments • “Semisolid preps intended for external application to the skin or mucus membranes.”  May be medicated or unmedicated.  Unmedicated ointments exhibit physical effects beneficial as protectants, emollients, and lubricants. 34 Ointment Bases - Classification 1. Oleaginous bases (hydrocarbon bases) - emollient effect, prevents escape of moisture, occlusive dressing, difficult to wash off (water immiscible); aqueous material may be incorporated but only in small amounts and with some difficulty. Examples:  Petrolatum (USP) (aka yellow petrolatum and petroleum jelly), Vaseline®  Yellow Ointment (USP) (yellow wax from honeycomb), 50 g plus 950 g petrolatum, aka “simple ointment” 2. Water-removable bases (water-washable bases) - o/w emulsions resembling creams. Easily washed from skin. Can be diluted with aqueous solutions. Capable of absorbing serious discharges. 3. Water-soluble bases do not contain oleaginous components. Completely water washable (“greaseless”). Tend to soften greatly with the addition of water, so they are not used to incorporate aqueous solutions. They are used for the incorporation of solid substances. 35 Selection of the Appropriate Ointment Base Will Depend On:  Desired release rate of drug from base.  Desirability of topical or percutaneous drug absorption.  Desirability of occlusion of moisture from skin.  Stability of drug in base.  Effect of drug on consistency of base.  If water-washability is desired.  Characteristics of surface to which it is applied. 36 Creams “Semisolid preps containing one or more medicinal agents dissolved or dispersed in either a w/o emulsion or o/w emulsion or in another type of water-washable base.” Why would a patient/physician prefer a cream to an ointment? - Creams are easier to spread and remove. 37 Universe of Topical Medications Basic components of all topical preparations are powder, water, oil, emulsifier A = powder can be a protective drying agent, lubricant or carrier for locally applied drugs B = powder + oleaginous material C = oleaginous materials only D = oil phase + w/o emulsifier  capable of absorbing aqueous solutions of drugs E = water + oil + w/o emulsifier  w/o emulsion F = water + oil + w/o emulsifier w/o cream G = water + oil + o/w emulsifier  o/w cream water + oil + o/w emulsifier  o/w lotion I = water  an aqueous liquid prep H= J = water + powder  lotion (e.g. calamine lotion) Fig. 17-20 from Martin’s Physical Pharmacy 38 CONCEPTS TO REVIEW 1. What is an emulsion? The two types are ____ and ______ 2. How can you tell one type from another? 3. Be familiar with the three different types of emulsifying agents , properties and general rules. 4. Stability of an emulsion is characterized by ____, _____, _____, and ______. 5. How can we reduce creaming in emulsions? 6. What is coalescence and how can we prevent this phenomena? 7. Common dosage forms for semisolids (gels, emulsions) include _____, _____, and ____. 8. Be able to calculate drug diffusivity from a gel 9. Understand basic components of all topical preparations 33