PHB216 Emulsions (PDF)

PHB216 EMULSIONS _ Pharmaceutical Liquid-Liquid Systems LEARNING OBJECTIVES discuss various explain the formulation At the end of these mechanisms of emulsion...

PHB216 EMULSIONS _ Pharmaceutical Liquid-Liquid Systems LEARNING OBJECTIVES discuss various explain the formulation At the end of these mechanisms of emulsion principles of liquid-liquid lectures students should instability and strategies systems and their use in be able to – to improve stability of pharmaceutical products emulsions apply HLB concept to Aulton – Design and formulate oil in water REFERENCES manufacture of and water in oil medicines emulsions Martin - Physical Pharmacy and Pharmaceutical Sciences 2 Pharmaceutical use of LL systems Topical LLS products  pharmaceutical creams and lotions  medicated, non-medicated  anti-inflammatory, antibacterial, antifungal  moisturizing, softening, cosmetics  aqueous- based, oily  semi-solids, liquids 3 Injectable LLS products  Intravenous (IV) lipid emulsion (o/w)  nutritional energy source, essential fatty/a & triglycerides  Intramuscular - often w/o to delay/control release  Subcutaneous - either o/w or w/o emulsion  Must be sterile  small dispersed particle size (eg 100-200 nm)  incorporate poorly water soluble drugs in lipid phase of emulsion 4 Oral LLS products  For a poorly water soluble drugs – example : cyclosporin, griseofulvin and steroids – dissolve drug in the oil phase  can avoid solid phase dissolution which can often limit the rate of absorption  emulgents present in formulation - changes in biochemical barrier (e.g. pgp) and physical barrier (tight junction)  may need large volume, poor taste, compliance  Ideally, can put oral emulsion in a capsule 5  Liquid- Liquid systems - Definitions Liquid (internal phase) Liquid (external phase)  2 immiscible liquid phases - one dispersed as liquid globules in the other liquid – a dispersed system  Dispersed phase = internal phase  Dispersion medium = external phase Oil in water (O/W) system = Oil dispersed phase; Water is the continuous phase Water in oil (W/O) system = water is the internal phase; oil is the external phase Quiz – If blue is water and red is oil, what type of LLS is represented in the above diagram? How can this be checked? 6  Identify w/o or o/w system? Dilute it with water - can mix with external phase Ions – check the conductivity, o/w system can conduct electric current especially where ionic surfactants are present use conductivity meter to check it Colour it with a dye – mix with water-soluble dye  dye dissolve into cream water is the external phase  o/w system Emollient - Feel it - creamy or greasy 7 Emulsification Emulsions are highly unstable systems  Two immiscible phases  Large interfacial surface area  High interfacial free energy  Droplet-droplet interactions  Flocculation, coalescense, cracking, 2 phase separation  Emulsification is the addition of a third component to make it a stable dispersed system  the “third” component = emulsifying agent (s) – emuls (Latin) – milked out 8 Desired properties of an emulgent  quickly adsorb around internal phase  form a stable, coherent film  provide mechanical barrier  reduce interfacial tension   effective at relatively low  impart electrical potential on concentrations droplet surface  non-toxic  increase viscosity  non-irritant  non-interacting  inexpensive 9  Classification of emulgents Traditionally, based on the source/origin: SOURCE Example ANIMAL WOOL FAT VEGETABLE ACACIA MINERAL Ca(OH)2 , Bentonite SYNTHETIC SURFACTANTS 10 Type of film produced at the interface EMULGENT CLASS FILM Finely divided solids Particulate Hydrophilic colloids Multi-molecular Surface active agents Mono-molecular (SAA) 11 1. Finely divided solids as emulgent  stabilize an emulsion by adsorbing at the interface  form a physical barrier (film) around the dispersed droplets to prevent coalescence  Interfacial film is particulate – e.g. powdered silica, bentonite clay particles  need sufficient adhesion for one another to form film around the dispersed droplets  finely-divided solids generally produce o/w emulsions 12  Preferential wetting theory of emulsification  Finely divided solid particles that are wetted to some degree by both oil and water phases  The phase in which the particle preferentially resides is the external phase  particles that are preferentially wetted by water form o/w emulsions  particles that are preferentially wetted by oil form ?? w/o emulsions 13  Bancroft rule of emulsification  Type of emulsion formed depends on relative solubility of the emulsifying agent in two phases  the phase in which it is more soluble being the continuous (external) phase  Thus, an emulsifying agent which is preferentially soluble in water  o/w emulsion  This type emulgent of has a high HLB value (more hydrophilic than lipophilic)  Low HLB value – more lipophilic, less hydrophilic  w/o emulsion  HLB = Hydrophilic Lipophilic Balance 14  2. Hydrophilic colloids and macromolecules as emulgents  Forms strong multi-molecular film  prevent coalescence of internal phase globules  film must break before drug is released  drug may be trapped in internal phase  potential for absorption and bioavailability problems  cause a significant  viscosity of the external phase which  stability of emulsion 15  Hydrophilic colloid examples : – methylcellulose, gum acacia, high M.W. polysaccharides: modified starch, pectin, alginates  Naturally occurring and so highly variable – may be problematic  polysaccharides are quite popular for internal emulsions as they have no taste problems  macromolecule examples – proteins, gelatin, egg yolk, lecithin, gum 16 3. SURFACE ACTIVE AGENT- (SAA)  Surface active agents  surface tension because of their adsorption at the oil-water interface  forms a flexible monomolecular film  complex, closely-packed, condensed film at the interface  film should be flexible so that it can reform rapidly if broken or disturbed  Quiz - Why do you think SAA can reside at the interface? 17  Characteristic feature of ALL surfactants - AMPHIPHILES 1. one portion of the molecule is polar (hydrophilic) 2. the other non-polar (lipophilic)  2 solubility characteristics within a single molecule  The relative size and characteristic of the polar and non- polar portions of the surfactant molecule will determine the type and quality of the emulsion produced 18  SAA Examples  Sodium lauryl sulphate  Cetrimide (cetromonium Br)  Cetostearyl alcohol  Polyoxyethylene sorbitan mono-oleate  Dodecylamine Hydrophilic groups  Sulphonate (SO3-)  quaternary ammonium compds (+NR3)  Polyoxyethylene (-CH2CH2O-)n Hydrophobic groups  Alkyl acids/alcohols/amines  Hydrocarbon-based fatty acid chain 19  How does SAA stabilise an emulsion? SAA No SAA  electrical repulsion – ionic surfactants cationic, anionic  steric repulsion – non-ionic surfactants 20  STERIC REPULSION - non-ionic SAA Oil droplet ELECTRICAL REPULSION – ionic SAA + + + + 21  + + ++ Ionic (charged) surfactants  charged surfactants tend to promote o/w emulsions – water is the preferred medium for ions  anionic or cationic surfactants produce oil in water creams and lotions (topical products) – e.g. Aqueous cream APF , Cetrimide lotion APF  charged surfactants are not generally used in oral emulsions - laxative effect 22  Anionic surfactants  Fatty acid salts (soaps)  Univalent alkali (NaOH) + fatty acid univalent soaps – stabilises aqueous emulsion (o/w) e.g. sodium oleate  Divalent alkali [Ca(OH)2] + fatty acid divalent soaps stabilise oily emulsions (w/o) – e.g calcium oleate  precipitate out as free fatty acid in acidic pHs – more stable in alkaline medium  Incompatible with cationic drugs 23 Cationic surfactants Cetylpyridinium chloride  fatty amine salts (or) ammonium salt  Incompatible with anionic drug complexation precipitation  Used in antiseptic creams due to antimicrobial properties (Cetrimide) Cetrimide  More irritating to skin than anionics and non-ionics  also used in hair conditioners and fabric softeners – bad hair day due to charge repulsion 24  Non-ionic surfactants  Non-charged (negligible) - e.g. cetomacrogol  wide range of compatibility  generally less toxic, less irritating  less sensitive to heat electrolytes and pH variation  more expensive  used in foods, drinks, pharmaceuticals and skin-care products, some suitable for parenteral product  hydrophobic moiety - a fatty acid/alcohol (C12-18)  hydrophilic moiety -alcohol/ethylene oxide (- OCH2CH2groups Glycerylmonostearate Glycerylmonooleate 25 Sorbitan Esters (Spans) Polysorbates (Tweens)  polyethylene glycol derivatives of the  Produced by esterification of one or sorbitan esters more of the hydroxyl groups of  Hydrophilic properties o/w sorbitan with fatty acid  Tween 80 – polyoxyethylene-  Lipophilic properties w/o emulsion sorbitan-monooleate  care with choice of preservatives  SPAN 80 – sorbitan mono-oleate – complexation with benzoate, (C18:1). Span 40 – sorbitan mono - parabens palmitate(C16:0) 26  Other surfactants  Lecithin is amphoteric SAA  Charge depends on the pH cationic at low pH anionic at high pH food emulsifier, IV emulsions Betain phosphatidylcholine 27  EMULGENT SYSTEM  combination of emulsifying agents used for greater stability Oil  e.g: use of a more hydrophilic Tween in combination with a more hydrophobic Span  a predominantly hydrophilic emulsifying agent in the aqueous phase  a predominantly hydrophobic emulsifying agent in the oily phase  complex, closely-packed, condensed film at the interface Ref: Martin’s Physical Pharmacy 28 Emulsion stability  Most pharmaceutical emulsions have dispersed phase droplets ranging from 100nm - 100m  a very large interfacial area  The change in interfacial area requires the input of energy  This energy is supplied by - – use of a mortar and pestle – micron particle size – homogenizer – 500 nm – ultrasonicator - 9) o/w emulsions 57  Preservatives in L-L systems  The emulsion should be formulated with a preservative to prevent microbial instability  partitioning of the preservative can occur between the oil and water phases and concentration used must allow for this  partitioning of preservatives between the two phases will decrease the effective concentration of the preservative(s)  It is important to achieve an effective concentration of preservative in the aqueous phase where most microbial growth occur 58 Preservative effectiveness is affected by:  pH - preservative must be in an un-ionized state to penetrate the bacterial membrane. – e.g. the activity of weak acid preservatives  as the pH of the aqueous phase  e.g. benzoic acid must be in acidic conditions  Preservative molecules must not be “bound” to any of the emulsion components including SAA – Non-ionic SAAs reduce activity of some preservatives, such as chlorocresol, hydroxybenzoates and benzoic acid  the emulsion type, the nutritive value of the product, degree of aeration, type of container can also affect preservative choice 59  Microemulsions  In brief, these are emulsions of very small particle size  Dispersed globules are of colloidal dimensions – – 1nm - 1µm (nano - microemulsion)  homogeneous, transparent or translucent systems  generally optically clear/faint blue tinge and very low viscosity  solubilization involves the use of SAA to make a poorly soluble drug more soluble  need much larger amounts of surfactant – restricts choice of acceptable components  volume of dispersed phase varies from 0.2-0.8 60  Useful as drug delivery systems to increase the bioavailability of drugs that are poorly soluble in water by incorporating them into the internal phase  This technology has been applied to transdermal drug delivery systems with some success, and also to ocular, IV and oral systems  Currently used in cosmetic science, foods, dry cleaning and wax polishing products 61  SEDDS and SMEDDS  Self (micro-) emulsifying drug delivery systems  isotropic mixture of oils, surfactants, co-solvents (EtOH,PEG)  dilution in aqueous GI environment to form o/w emulsion/microemulsion with gut fluid and agitation  enhanced oral bioavailability of lipophic drugs - cyclosporin, vit E, ibuprofen)  uniform drug absorption and plasma levels  protect drug degradation and gastric irritation in the gut environment  high concentration of surfactants (30-60%) - irritation, toxicity  Potential problems with SAA - de-fatting of tissues, cell membrane damage, haemolysis, necrosis, purgative effect.  Limited number of ‘approved’ surfactants for internal use 62  Multiple emulsions  More complicated emulsion systems may exist, e.g. w/o/w.  In this type an oil droplet enclosing a water droplet may be suspended in water.  Oil layer between two aqueous phases can behave like a rate controlling membrane  These have lower viscosity and, hence, are easier to inject.  Can also have o/w/o – delayed-action drug delivery system 63  Practice questions 1. LLS are inherently unstable systems. True or false. Discuss. 2. Briefly describe 3 mechanisms of emulsion instability. Suggest 3 approaches to minimize emulsion instability. 3. Choice of emulgents and method of manufacturing can affect physical stability of emulsions. How? 4. Creams and lotions include labelling instruction such as “store below 30C”. Why? Explain. 64