DDS lecture 7 content

Emulsions

dispersion in which the dispersed phase is composed of small globules of a liquid, distributed throughout a vehicle in which it is immiscible

Oil in water (o/w) emulsion

• oils, petroleum hydrocarbons, or waxes are dispersed in water

• external phase: oil

• internal phase: water

• generally formed if the aqueous phase >45% of the total weight

• hydrophilic emulsifier is used

  • emulsifier must be miscible with larger/external phase

Water in oil (w/o) emulsion

• water or aqueous solutions are dispersed in an oleaginous medium

• aqueous phase constitutes <45% of the total weight

• lipophilic emulsifier is used

Stability

• emulsions are thermodynamically unstable

• separates into two phases

• instability:

  • creaming (better than coalescence + breaking)

  • coalescence

  • phase inversion

• must have appropriate emulsifier to prevent instability

Creaming

• dispersed droplets merge and rise to the top or fall to the bottom of emulsion

• result: lack of drug distribution

• creaming in o/w emulsions characterized by oil globules gathering and rising to the top (oil is less dense than water)

• reversible by shaking

• is reversible due to protective film around droplets which prevent coalescence

Coalescence

• breaking

• irreversible - film around individual droplets are destroyed

• viscosity alterations may help stabilize droplets and minimize tendency to coalescence

• to avoid, use optimum phase: volume ratio

• internal volume should be less than external volume

Phase inversion

• change in type of emulsion (o/w into w/o, vice versa)

• sign of instability

Emulsifying agents

• emulsifying agents concentrate and are adsorbed at the oil:water interface to provide a protective barrier around the dispersed droplets

• stabilize the emulsion by reducing the interfacial tension in the system

• some also impart charge on droplet surface, reduce contact between droplets, decreasing potential for coalescence

Chemical structures classifications of emulsifying agents

• synthetic

• natural

• finely dispersed solids

• auxiliary agents

  • secondary emulsifying agent (support action of primary)

Mechanisms of action classifications of emulsifying agents

• surface active agents (adsorb at o:w interface, form monomolecular layer)

• hydrophilic colloids (forms multimolecular layers at interface)

• finely divided solid particles (adsorp at interface and forms a layer of particles around the droplets)

Surfactants

• synthetic emulsifying agents

• hydrophilic and lipophilic part

• moves to liquid: liquid interface, reducing surface/interfacial tension in the system

Anionic surfactants

• synthetic emulsifying agent

• soaps and detergents

• subject to hydrolysis, less desirable than stable detergents

• surface active groups contain carboxylate, sulfate and sulfonate groups

• sodium lauryl sulfate (SLS)

  • long alkyl chain sulfonates less susceptible to hydrolysis

Cationic surfacetants

• synthetic emulsifying agents

• bactericidal

• long chain amino and quaternary ammonium salts

• both cationic and anionic emulsifiers used in topical o/w emulsions, but cationic less frequently used

Nonionic surfactants

• synthetic emulsifyin agent

• most frequently used

• superior in compatibility, stability, lack of toxicity

• neutral pH - resistant to addition of acid and electrolytes

• most commonly used are polyoxyethylene sorbitan fatty acid esters

  • Span

  • Tween

Plant/Animal sources of emulsifiers

• natural emulsifying agents

• most from a hydrated lipophilic colloid (hydrocolloid)

• form a multi-molecular layer around the emulsion droplets

• little to no effect on interfacial tension

• protective colloid effect and reduce potential for coalescence by

  • providing protective sheath around droplets

  • imparting charge to dispersed droplets

  • swelling to increase viscosity of system (less likely to merge)

Classified emulsifying agents

• natural emulsifying agent

• vegetable derivatives: acacia, tragacanth, agar, pectin, carrageenan

• animal derivatives: gelatin, lanolin, cholesterol, lecithin

• semi-synthetic agents: methylcellulose (MC), carboxymethylcellulose (CMC)

• Synthetic: carbopols

Finely divided or dispersed solid particle emulsifiers

• form particulate layer around the dispersed particle

• most will swell and increase viscosity to reduce interaction between dispersed droplets

• most o/w but some may work for w/o

• ex. bentonite,- fatty acids (stearic acid) Veegum, magnesium hydroxide, aluminum hydroxide, magnesium trisilicate

Auxiliary emulsifying agents

• Fatty acids (stearic acid)

• Fatty alcohols (Stearyl or Cetyl alcohol)

• Fatty esters (glyceryl monostearate)

• Stabilizes emulsions by thickening formulation

• weak emulsifying properties, thus used in combination with other emulsifiers

Hydrophile-Lipophile balance (HLB)) system

• system developed to assist in deciding how much and types of surfactants to add to make an emulsion

• arbitrary scale

• numbers determined experimentally

• low number = few hydrophilic groups, more lipophilic

  • Span: oil soluble, used for w/o emulsion

• High number = large number of hydrophilic groups, more hydrophilic character

  • Tweens: water soluble, used for o/w emulsions

Span

• emulsifying agent for water in oil emulsions

• oil soluble

• low HLB

• non-ionic surfactant

Tween

• emulsifying agent for oil in water emulsions

• high HLB

• water soluble

• non-ionic surfactant

HLB value for emulsifying agents for w/o emulsions

3-8

HLB value for emulsifying agents for o/w emulsions

8-16

HLB value for detergents

13-16

HLB value of surfactant system

Continental/Dry gum/4:3:2 method of compounding emulsions

1. prepare initial emulsion from oil, water and vegetable derived hydrocolloid or gum type emulsifier (usually acacia)

2. primary emulsion = 4 parts oil, 2 parts oil, 1 part emulsifier

   1. Emulsifier triturated with oil until powder wetted thoroughly

   2. add water, vigorously triturate

   3. creamy white emulsion made

English/wet gum method

1. emulsifier triturated with water

2. oil added in portions while triturating

• more difficult than dry gum, but yields more stable emulsion

• 4 parts oil, 2 parts water, 1 part emulsifier

Adding ingredients to primary emulsion

• solid substance

  • API preservative, colors, generally dissolve and added as solution to primary emulsion

• volatile ingredients added when product is cool

• substances which may reduce physical stability

  • ex. alcohol, which will precipitate the gum, should be added near end

• after incorporation of all ingredients, blend to ensure uniform distribution of medicaments

• viscosity enhancers can be added to increase stability

  • o/w: hydrocolloids

  • w/o: viscous oils, fatty alcohols, fatty acids

Adding ingredients to commercial products (w/o)

• w/o emulsions, oils, and insoluble powders can be incorporated directly into external phase with spatula and pill tile or low heat

• adding aqueous soluble materials to w/o emulsion more difficult

• excess emulsifier must be present to accommodate more water

• aqueous solution of drug added to emulsion with pill tile and spatula

Adding ingredients to commercial product (o/w)

• o/w emulsions - good levigation agents for aqueous insoluble substances needed

• ex. glycerin, propylene glycol, polyethylene glycol (PEG) 300 or 400, alcohol

• use salt form of API if available

• external phase incorporation is easy with pill tile and spatula

• heat may be needed

Flavoring emulsions

• for o/w emulsions, if using flavoring oil, it may concentrate into internal phase

  • strength in external phase is less

• to reduce partitioning, flavoring oils may be mixed with small amount of emulsifier, then added

• 3-5 times as much emulsifier as oil should be used

  • or mix with ethanol or glycerin

Determination of emulsion type

• dilution test

• dye test

• drop test

Dilution test

• dilute with water

• o/w emulsion will be stable

• w/o will separate and break

Dye test

• add water soluble dye to sample and mix

• if uniform color, o/w emulsion

• globular distribution shows w/o emulsion

Drop test

• put drop of emulsion on water

• if spread out - o/w bc miscible

• if stays drop - w/o

Antimicrobial additives

• methylparaben

• propylparaben

• benzoic acid

• benzalkonium chloride

Antioxidant additives

• Ascorbic acid

• butalyted hydroxyanisole (BHA)

• butylated hydroytoulene (BHT)

• 1-tocopherol

liquid in liquid

emulsion

solid in liquid

suspension

solid in solid

mixture (powders and granules)

Suspensions

• a heterogenous mixture in which the internal phase is dispersed throughout the external phase through mechanical agitation, with. the use of certain excipients or suspending agents

• two-phase system consisting of undissolved or immiscible material dispersed in a vehicle

• will eventually settle

Advantages of suspensions

• chemical stability

  • some compounds stable when suspended but unstable when dissolved

• organoleptic reasons

  • disagreeable tastes/smells often attenuated when in suspension vs solution

• ease of swallowing

  • liquid

  • easier for infants, children, elderly patients

• higher bioavailability

Bioavailability order

Solution > Suspension > Capsule > Compressed Tablet > Coated Tablet

Disadvantages of suspensions

• physical stability, sedimentation, and compaction may cause problems

• bulky

  • sufficient care must be taken during handling, transport

• difficult to formulate

• uniform and accurate dose cannot be achieved unless suspension packed in unit dosage form

Ideal properties of suspensions

• settle slowly and readily disperse upon gentle shaking

  • should not be stirred

• particle size remains constant throughout long periods of standing

• pour readily and evenly from its container

• physically and chemically stable

• resistant against microbial contamination

• good organoleptic properties

Applications of suspensions

• applicable for insoluble/poorly soluble drug

• prevent degradation of drug or improve stability of drug

• mask unpleasant/bitter taste of drug

• can be formulated for topical application

• can be formulated for parenteral application

  • control rate of drug absorption

  • vaccines, X-ray contrast agents

Routes of administration of suspensions

• oral suspensions

• topical suspensions

• parenteral suspensions

• ophthalmic suspension

Stokes’ law

• speed with which particles settle out of a liquid medium is dependent on a constant factor (K) and the radius of the particles

  • the bigger the particle, the faster it will fall out of suspension

• particle moving through viscous liquid attains constant velocity (sedimentation rate)

  • very slow for particles with density close to liquid density, particles with small diameter, or where viscosity is high

Stokes’ Equation

dx/dt = rate of settling

d = diameter of particle

Pi = density of particles

Pe = density of medium

g = gravitational constant

N = viscosity of medium

Factors affecting sedimentation

• particle size diameter

  • smaller diameter = slower rate

• density difference between dispersed phase and dispersion media

  • lower density difference = slower sedimentation rate

• viscosity of dispersion medium

  • increase in viscosity = decrease settling

  • greater increase in viscosity leads to issues like pouring, syringibility, redispersibility of sediments