Untitled Quiz

Emulsions (Liquid-Liquid system)

• Emulsions are two-phase systems
• Two immiscible liquids
• One liquid is dispersed throughout the other in fine droplets
• Typically stabilized by an emulsifying agent
• Heterogeneous system
• Consist of at least one immiscible liquid dispersed in another liquid
• Droplets have a diameter generally exceeding 0.1 µm
• Thermodynamically unstable system
• Contains at least two immiscible liquid phases
• One phase dispersed as globules in the other
• Stabilized by a third substance (emulsifying agent)
• Exhibit an acceptable shelf life near room temperature
• Internal phase (disperse phase or discontinuous phase)
• Surrounded by an external continuous phase
• Occupies no more than 74% of total emulsion volume
• Emulsifier added to increase droplet longevity in immiscible liquids
• It's a stabilizer of the internal phase droplets (globules)
• Composed of hydrophilic (oleophobic) and hydrophobic (oleophilic) portions
• Often called amphiphilic (water and oil loving)
• Common emulsions involve water and oil or a lipid

Types of Emulsions

• Simple emulsions (macro emulsions)
  • Diameter greater than 0.1 µm
  • 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/Nano emulsions
  • Thermodynamically stable
  • Optically transparent
  • Mixtures of a biphasic oil-water system
  • Stabilized with surfactants
  • Size range 0.01-0.1 µm

Introduction

• Usually only one phase persists in droplet form for a prolonged period (internal phase)
• Internal phase is surrounded by external continuous phase
• Internal phase can occupy no more than 74% of emulsion volume (can exceed if not monodisperse)
• Emulsifier increases droplet lifetime in immiscible liquids and acts as a droplet stabilizer
• Emulsifiers are amphiphilic (have both hydrophilic and hydrophobic parts)

Multiple Emulsions

• Oil in water in oil (o/w/o)
• Water in oil in water (w/o/w)
• Emulsion type can invert (change from o/w to w/o or vice versa) during inversion, they typically form simple emulsions. A w/o/w emulsion normally yields an o/w emulsion.

Emulsion Type

• Phase volume ratio (relative amount of oil and water) determines relative number of droplets and collision probability
• The phase present in greater amount usually becomes the external phase
• Water-soluble emulsifiers generally favor o/w emulsions
• Lipid-soluble emulsifiers generally favor w/o emulsions

Applications

• Oral dosage forms (make medicinal agents more palatable)
• High efficacy (BA or absorption) for unabsorbable macromolecules (e.g., heparin and insulin)
• Topical emulsions (control viscosity, appearance, and greasiness of cosmetics)
• Water washable drug bases and general cosmetic purposes
• Treatment of dry skin and emollient applications
• Intravenous administration of lipid nutrients
• Radiopaque emulsions as diagnostic agents in X-ray examination
• Intramuscular depot injections
• Emulsification of perfluorinated hydrocarbons useful as oxygen carriers in blood replacements
• Dilution with safe, inexpensive diluents (e.g., water) for economic reasons

Formulation Components

• Lipid phase
• Emulsifying agents (surfactants)
• Auxiliary emulsifiers (hydrophilic colloids, finely divided solids)
• Viscosity modifiers
• Antimicrobial preservatives
• Antioxidants

Surface Active Agents (Surfactants)

• Substances with both hydrophilic and hydrophobic regions
• Soluble in both oil and water
• Hydrophilic portion oriented toward polar solvent (water)
• Hydrophobic portion oriented toward non-polar solvent (oil)
• Lower interfacial tension (allows for easier emulsification)
• Classified into anionic, cationic, nonionic, amphoteric based on charge

Anionic Surfactants

• Negatively charged
• Sodium lauryl sulfate is commonly used in o/w emulsions
• Alkali metal soaps (e.g., sodium oleate) often stable w/o emulsions due to low water solubility
• Triethanolamine stearate produces stable o/w emulsions

Cationic Surfactants

• Positively charged
• Expensive
• Used as preservatives due to bactericidal action (sterilizing contaminated surfaces and emulsions)

Nonionic Surfactants

• Neutral (no charge)
• Water-soluble (e.g., polysorbates) often used in o/w emulsions
• Water-insoluble (e.g., sorbitan esters) often used in w/o emulsions

Ampholytic Surfactants

• Possess both cationic and anionic groups
• Stability dependent on pH of the medium
• Lecithin is often used.

Hydrophilic-Lipophilic Balance (HLB) Concept

• System for determining the suitability of a surfactant for a specific emulsion
• Based on the balance between hydrophilic and lipophilic properties of the surfactant
• HLB value can be determined experimentally or calculated from chemical structure
• Values depend on mixing ratios of polyhydric alcohols and fatty acids

Methods for determining Emulsion Type

• Dilution test (useful for liquid emulsions)
• Dye test (fails for ionic emulsifiers)
• CoCl₂/filter paper (fails if emulsion unstable or breaks)
• Fluorescence (not always applicable)
• Conductivity (fails for non-ionic emulsions)

Micro Emulsions

• Dispersions of insoluble liquids appearing clear and homogeneous
• Often called solubilized systems
• Micellar state (oil dissolves in interior of micelle because of hydrophobic nature)

Emulsion Formation Methods

• Dispersion method (separation into droplets by heat, mechanical agitation, ultrasonic vibration, or electricity)
• Condensation method (vapor of a liquid into external phase, limited to dilute emulsions of materials with low vapor pressure)
• Phase inversion method (transition through different temperatures, depends on emulsifier concentration, often stable)
• Low energy emulsification (only portion of internal or external phase is heated, often quite stable with small droplets)

Mechanical Equipment for Emulsification

• Mechanical stirrers (simple for low viscosity systems, more vigorous types for higher viscosity)
• Homogenizers (high pressure forces mixture through small orifice to create a uniform emulsion)
• Ultrasonifiers (ultrasonic vibration to produce dispersion, expensive and limited capacity)
• Colloid mills (high shear between rotor and stator for very fine dispersions)

Production Aspects

• Foaming during agitation (often reduces surface tension for water-soluble emulsifiers)
• Chemical stability (prevention of hydrolytic or oxidative reactions within components)
• Safety (consideration regarding toxicologic clearances for emulsion ingredients)

Stability of Emulsions

• Thermodynamically unstable due reduction of interfacial area by coalescence.
• Stability defined in terms of maintaining the same number of particles per unit volume, invariant with time.
• Product shelf life depends on kinetic stability.
• Stability is generally temperature-dependent

Symptoms of Emulsion Instability

• Creaming (upward movement of denser phase)
• Flocculation (reversible aggregation of droplets)
• Coalescence (irreversible aggregation into larger droplets or complete phase separation)
• Phase inversion (transition from o/w to w/o, or vice versa)

Flocculation

• Revesible aggregation of droplets as 3-dimensional clusters.
• Influenced by surface charges on droplets.
• Requires sufficient emulsifier to prevent coalescence
• Reversibility depends on interaction strength between particles (e.g., electrolytes, ionic emulsifiers).
• often used in practical o/w and w/o emulsions

Creaming

• Particle movement due to differences in density.
• Rate of creaming is described using Stoke's equation (V = d²*(pi-pe)g / 18η)
• . Rate depends on particle size, density difference, viscosity of medium
• Can be reversible (reconstituted by shaking).

Coalescence

• Irreversible aggregation leading to larger droplets and eventually complete phase separation
• Reduced by mechanical barriers

Phase Inversion

• Change in emulsion type (e.g., o/w to w/o)
• Can be induced by adding electrolytes or by changing phase ratios of the emulsion components
• Stability can be affected.
• High-precision critical point needed to produce stable emulsions.

Assessment of Emulsion Shelf Life

• Techniques for speed-up stability program include stressing the emulsion under various conditions
• No quick tests exist to determine the stability of emulsions precisely in the beginning.
• Common stress conditions: Aging and temperature (cycling between different temps), Centrifugation, Agitation

Stress Conditions

• Aging and Temperature Cycling
• Centrifugation
• Agitation

Parameters for Evaluation of Emulsion Stability

• Chemical parameters (e.g., presence of decomposition products)
• Physical parameters (e.g., phase separation, viscosity, and electrical conductivity)
• Particle size analysis

Practical Recommendations for Shelf life predictions

• Develop a realistic program for stability assessment.
• Carefully observe emulsion behavior under various conditions and reasonable time spans.