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PHARMA

CHAPTERWISE
NOTES

Pharmaceutical Technology &

Modern Pharmaceutics

Emulsions

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 EMULSIONS (LIQUID-LIQUID SYSTEM)

●​ An emulsion is a mixture of two immiscible liquids, where one is dispersed in the other

⚠️
as tiny droplets.
●​ Thermodynamically unstable → tends to separate unless stabilized by an
emulsifier.

Phases of an Emulsion

🔸 Phase Type 💧 Description

Disperse Phase Internal / Discontinuous phase (droplets)
Continuous Phase External phase (surrounds the droplets)

Types of Emulsions

🟠 💧
1.​ O/W (Oil-in-Water)​
Oil droplets in water​
➤ Found in: Lotions, vanishing Creams, Milk

💧 🟠
2.​ W/O (Water-in-Oil)​
Water droplets in oil​
➤ Found in: Butter, Cold Creams
3.​ Multiple Emulsions​
• O/W/O → Oil in Water, then in Oil​
• W/O/W → Water in Oil, then in Water​
➤ Uses: Controlled Drug Release, Cosmetics

Emulsifiers (Stabilizers)

●​ Role: ↓ Surface tension b/w two immiscible liquids

●​ Help form & stabilize the emulsion

Size & Appearance

Type Droplet Size Appearance

Opaque Emulsion 0.25 – 10 µm White, milky
Microemulsion 10 – 75 nm Transparent
Micelles 5 – 20 nm Clear, not true emulsion

📌 Note: Micelles = lipid-surfactant structures, not droplets.

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🔹 O/W = Washable, non-greasy, absorbs quickly​
🔹 W/O = Greasy, occlusive, better for dry skin​
🔹 Microemulsions = Thermodynamically stable but require surfactants
Theory of Emulsification:

1. Surface Tension Theory

●​ Liquids naturally minimize surface area → form spherical droplets.

●​ Interfacial tension exists between immiscible liquids, preventing droplet formation.
●​ Surfactants reduce this interfacial tension ↓​
⇒ Easier to break large droplets into smaller ones​
⇒ Prevents coalescence​
⇒ Stabilizes the emulsion
●​ Key Point: Lowering interfacial tension → ↑ emulsion stability

2. Oriented-Wedge Theory

●​ Emulsifying agents form a monomolecular layer around droplets of the internal

phase.
●​ These agents have both hydrophilic (water-loving) and hydrophobic (oil-loving) parts.
●​ If an emulsifier is more water-soluble → O/W (oil-in-water) emulsion forms.
●​ If an emulsifier is more oil-soluble → W/O (water-in-oil) emulsion forms.
●​ Key Point: The continuous phase is the one in which the emulsifier is more soluble.

3. Plastic or Interfacial Film Theory

●​ Emulsifying agents form a thin film at the oil-water interface, surrounding droplets of
the internal phase.
●​ This prevents the droplets from coming into contact and merging (coalescence).
●​ A strong, flexible film improves emulsion stability.
●​ Like the wedge theory, water-soluble agents form O/W emulsions, while oil-soluble
agents form W/O emulsions.

4. Electrical Repulsion:

●​ Surfactants stabilize emulsions by forming an electrical

double layer around droplets.
●​ Charged emulsifiers orient themselves at the interface,
creating a surface charge that repels other droplets.
●​ This prevents coalescence and increases emulsion stability.

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 Types of Emulsifying Agents

Type Mechanism Examples

Surface-active Reduce interfacial tension Sodium lauryl sulfate, Tween 80,
agents and form a monomolecular Span 20
film.

Hydrophilic Form multimolecular films Gelatin, Acacia, Alginate

colloids and provide electrostatic
stabilization.

Finely divided Form solid-particle films at Bentonite, Magnesium hydroxide,

solids the interface, acting as Aluminum hydroxide
physical barriers.

Bancroft’s Rule, states that the solubility of an emulsifier determines the type of emulsion
formed:

●​ A water-soluble emulsifier forms an o/w (oil-in-water) emulsion.

●​ An oil-soluble emulsifier forms a w/o (water-in-oil) emulsion.

It also explains different methods to determine the type of emulsion, summarized in Table:

Test Observation
Dilution test Emulsion dilutes only with its external phase. Useful for liquid emulsions only.

Dye test Water-soluble dye will dissolve in the aqueous phase whereas oil-soluble dye will
dissolve in the oil phase.
For example: Amaranth (o/w Emulsion), Scarlet/Sudan (w/o Emulsion).
Microscopic observation is helpful.
CoCl₂ filter Cobalt chloride paper (blue) turns pink with o/w emulsions.
paper test May fail if emulsion is unstable or breaks in the presence of electrolytes.
Fluorescence Under UV light, o/w emulsions show a dot pattern, while w/o emulsions fluoresce
test throughout. Not always applicable.
Conductivity When current is passed through an emulsion connected to a voltage bulb, the bulb
test glows if it is an oil-in-water (o/w) emulsion, as water is a good conductor of electricity.
Conversely, the bulb does not glow if it is a water-in-oil (w/o) emulsion, because oil is
a non-conductor of electricity. i.e.
o/w = current flow
w/o = current do not flow
o/w = current not flow (when purified water instead of potable water is taken)

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Gibbs Free Energy in an Emulsion

●​ Gibbs free energy (G) determines the stability of emulsions and suspensions.
●​ Emulsions contain two insoluble phases where internal phase droplets can undergo:
○​ Creaming (reversible separation)
○​ Cracking (irreversible merging of droplets to reduce G)

Gibbs Free Energy Equation: 𝐺 = 𝐴∆γ

Where:

●​ G = Gibbs free energy

●​ A = Total surface area of dispersed particles
●​ γ = Interfacial tension (repulsion between phases)

Key Principles

●​ Large G → Unstable system → Causes droplets to merge and reduce surface area (A).
●​ To create a stable emulsion, we need:
○​ Large surface area (A) for uniform dosing.
○​ Small interfacial tension (γ) to lower free energy (G).

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Factors Affecting Stability

●​ High γ and High G → Leads to aggregation of droplets (instability).

●​ Reducing γ (using emulsifiers/surfactants) → Lowers G, preventing droplet merging
and ensuring stability.
●​ Stable emulsions and suspensions require large A with low G for uniform and
consistent dosing.

FORMULATION COMPONENTS

Lipid Phase in Emulsions

●​ The oil portion of an emulsion, which can be natural or synthetic.

●​ Phase Ratio:
○​ Depends on drug solubility and required dosage form consistency.
○​ Low internal phase → More fluid emulsions.
○​ High internal phase → Thicker emulsions, requiring more emulsifier.

Emulsifying Agents: Three major classes:

1.​ Surfactants (Surface Active Agents) → Primary emulsifiers

2.​ Hydrophilic Colloids → Used as auxiliary emulsifiers
3.​ Finely Divided Solids → Act as stabilizers

1. Surfactants (Surface Active Agents)

●​ Molecules with hydrophilic (water-loving) and hydrophobic (oil-loving) regions.

●​ Function:
○​ Reduce interfacial tension, making emulsification easier.
○​ Form monomolecular layers at the oil-water interface.
●​ Classification Based on Charge:

1. Anionic Surfactants (Negatively Charged)

●​ Example: Sodium Lauryl Sulfate (SLS) (Used for o/w emulsions).

●​ Alkali Metal Soaps:
○​ Sodium oleate (Na+ form) → o/w emulsions.
○​ Calcium oleate (Ca²⁺ form) → w/o emulsions (low water solubility).
●​ Triethanolamine Stearate → Produces o/w emulsions (e.g., vanishing cream).
●​ pH Sensitivity: Effectiveness varies with pH and electrolytes.

2. Cationic Surfactants (Positively Charged)

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 ●​ Examples: Quaternary Ammonium Compounds, Pyridinium Salts.
●​ Uses:
○​ Less common in emulsions due to high cost.
○​ Antimicrobial properties → Used in preservatives and sterilizers.

3. Non-Ionic Surfactants (Neutral Charge)

●​ Examples:
○​ Spans (Sorbitan Esters) → w/o emulsions (Water-insoluble).
○​ Tweens (Polysorbates) → o/w emulsions (Water-soluble).
●​ Advantages:
○​ Low toxicity → Suitable for oral and parenteral formulations.
○​ Stable in varying pH and electrolytes.
○​ HLB balancing: Often combined (Span + Tween) for optimal emulsion stability.

4. Ampholytic (Zwitterionic) Surfactants

●​ Contain both positive and negative charges depending on pH.

●​ Example: Lecithin (Used in parenteral emulsions).

Hydrophilic-Lipophilic Balance (HLB):

●​ Emulsifiers are selected based on their hydrophilic (water-attracting) and lipophilic

(oil-attracting) nature.
●​ HLB values help classify surfactants based on their affinity for oil or water, making
emulsifier selection easier.

HLB Calculation Methods

1.​ For polyhydric alcohol fatty acid esters:

where,

○​ S = Saponification number of the ester

○​ A = Acid number of the fatty acid
2.​ For emulsifiers without saponification numbers (e.g., beeswax, lanolin derivatives):

where,
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 ○​ E = Weight percent of oxyethylene chains
○​ P = Weight percent of polyhydric alcohol groups

3.​ For emulsifiers with polyoxyethylene chains:

where, E is the weight percent of oxyethylene groups.

Application of Surfactants Based on HLB Value

HLB Value Application

1–3 Antifoaming agents
3–6 w/o (water-in-oil) emulsifiers
7–9 Wetting agents
8–16 o/w (oil-in-water) emulsifiers
13–15 Detergents
15–18 Solubilizing agents

Phase Inversion Temperature (PIT)

●​ At PIT, the surfactant shifts between oil and water phases due to temperature changes,
affecting stability and particle size.
●​ Key points about PIT:
○​ Maximum particle size reduction occurs near PIT.
○​ Surfactants that are water-soluble at room temperature may become oil-soluble
near PIT.
○​ During cooling, emulsifiers relocate to different phases, affecting emulsion
stability.
○​ If the temperature exceeds PIT during emulsification, a stable emulsion is
formed.

2. Hydrophilic Colloids

●​ These are water-sensitive polymers that act as:

○​ Primary emulsifiers
○​ Emulsion stabilizers
○​ Thickening agents

Types of Hydrophilic Colloids

1.​ Natural and Synthetic Clays

○​ Smectite clays (e.g., Bentonite, Montmorillonite)
■​ Swell in water and increase viscosity.
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 ■​ Require pH ≥ 6 to thicken solutions.
○​ Amphibole clays (e.g., Attapulgite)
■​ Thicken by particle interaction rather than swelling.
■​ Used in makeup formulations and suspensions.
2.​ Natural Gums and Synthetic Polymers
○​ Natural gums: Mostly polysaccharides (e.g., gum arabic, acacia, tragacanth).
○​ Synthetic hydrocolloids: Include cellulose derivatives (e.g., carboxymethyl
cellulose, hydroxypropyl methylcellulose).
○​ Carboxyl vinyl polymers: Provide yield value (ability to resist flow), improving
emulsion thickness and stability.

3. ​Finely Divided Solids:

· ​Finely divided solid particles can act as emulsifiers, particularly when used with
surfactants or macromolecules that increase viscosity.

●​ These solids help stabilize emulsions by forming a physical barrier around the
dispersed droplets, preventing coalescence.

Types of Finely Divided Solids:

1. Polar Inorganic Solids

●​ These are solid particles with high water-wetting ability.

●​ They promote oil-in-water (o/w) emulsions, where water is the continuous phase.
●​ Examples:
○​ Heavy metal hydroxides (e.g., aluminum hydroxide, magnesium hydroxide)
○​ Certain non-swelling clays (e.g., kaolin, bentonite)
○​ Pigments (e.g., titanium dioxide, zinc oxide)

2. Non-Polar Solids

●​ These are solid particles that are more oil-wettable.

●​ They promote water-in-oil (w/o) emulsions, where oil is the continuous phase.
●​ Examples:
○​ Carbon (e.g., activated charcoal)
○​ Glyceryl tristearate (a fat-based compound)

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 III. Antimicrobial Preservatives in Emulsions

●​ Emulsions contain water, lipids, carbohydrates, proteins, sterols, and phosphatides,

which can support microbial growth. To prevent contamination, antimicrobial
preservatives are added to emulsions.

Types of Antimicrobial Preservatives

Different types of preservatives are used in emulsions. The following table lists common
preservative groups and examples:

Type Example
Acids and acids Benzoic acid and salts, Propionic acid and salts, Dehydroacetic acid
derivatives
Alcohols Chlorobutanol, Phenoxy-2-ethanol
Aldehydes Formaldehyde, Glutaraldehyde
Formaldehyde Hexamethylenetetramine, Mono (and di-) methylol dimethyl
donors hydantoin
Phenolics Phenol, Cresol, α-Chlorometaxylenol
Quaternaries Methyl p-hydroxybenzoate, Propyl p-hydroxybenzoate, Butyl
p-hydroxybenzoate
Chlorhexidine salt, Benzalkonium chloride, Cetyl trimethyl
ammonium bromide
Mercurials Phenylmercuric acetate, Sodium ethylmercurithiosalicylate

IV. Antioxidants in Emulsions

●​ Many organic compounds are prone to autoxidation when exposed to air, and emulsified
lipids are particularly vulnerable. Several drugs incorporated into emulsions are also
susceptible to oxidation, leading to decomposition.

Effects of Autoxidation

●​ Unsaturated oils (e.g., vegetable oils) undergo rancidity, resulting in unpleasant odour,
taste, and appearance.
●​ Mineral oils and saturated hydrocarbons are less prone to oxidation.
●​ Autoxidation is a free-radical chain reaction, and it can be controlled by:
1.​ Removing oxygen.
2.​ Using free radical chain breakers.
3.​ Using reducing agents.

Selection and Use of Antioxidants

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 ●​ The choice of an antioxidant depends on safety, acceptability, and effectiveness.
●​ Common concentration range: 0.001 – 0.1% (w/v).
●​ Examples of widely used antioxidants in pharmaceuticals and cosmetics:
○​ Butylated hydroxyanisole (BHA)
○​ Butylated hydroxytoluene (BHT)
○​ L-Tocopherol
○​ Alkyl gallates

Antioxidant Remarks
Gallic acid Bitter taste
Propyl gallate Bitter taste
Ascorbic acid Commonly used in pharmaceuticals
Ascorbyl palmitate Suitable for lipophilic formulations
Sulfites Reducing agents
L-Tocopherol Well-suited for edible/oral formulations
Butylated hydroxytoluene (BHT) Strong antioxidant, pronounced odour
Butylated hydroxyanisole (BHA) Strong antioxidant, pronounced odour
4-Hydroxymethyl-2,6-di-tert-butylphenol Effective antioxidant

EMULSION FORMATION

●​ Emulsions are usually made using the dispersion method, which involves breaking up
the internal phase into small droplets and stabilizing them in the external phase.
●​ The process must be quick enough to prevent the internal phase from merging back
(coalescence).
●​ While droplet breakup happens quickly through physical force, stabilization depends on
time and temperature.

Methods of Emulsion Formation

🔹 Small-Scale Production (Manual) – Pestle & Mortar

Method Sequence of Mixing Use
Dry Gum / Continental Oil + Gum → then Water Common for fixed oils
Wet Gum / English Water + Gum → then Oil Forms mucilage first
Bottle / Forbes Method Oil + Gum → shake, then add Water Ideal for volatile / low-viscosity oils

🔹 Large-Scale Production (Mechanical)

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 Equipment Used Function
Homogenizers Reduces droplet size for stable emulsions
Electric Mixers Uniform mixing of phases
Colloidal Mills High shear dispersion of droplets
Ultrasonic Devices Uses sound waves to break droplets

Proportions for Emulsion Preparation

Oil : Water : Gum Ratios (Continental / Dry Gum Method)

Type of Example(s) Ratio (O:W:G)

Oil/Substance
Fixed Oils Almond, Arachis, Castor, Cod Liver Oil 4:2:1
Mineral Oils Liquid Paraffin 3:2:1
Volatile Oils Turpentine, Cinnamon, Peppermint 2:2:1
Oleoresins Male Fern Extract 2:2:1

Special Emulsion Type: Multiple Emulsions (w/o/w)

●​ Made in two steps:

●​ w/o emulsion is formed using a low HLB emulsifier.
●​ This w/o emulsion is mixed into water containing a high HLB emulsifier (HLB 12-14).

STABILITY OF EMULSIONS

●​ The stability of an emulsion depends on its physical properties and how they change
over time. An emulsion may become unstable due to temperature changes, time, or
external forces.
●​ When an emulsion becomes unstable, the following problems can occur:

Type Description Reversibility Phase Separation?

Creaming Droplets rise (↑) or settle (↓) due to density ✔ Reversible ✘ No

difference; no merging
Flocculation Droplets form loose clusters without merging ✔ Reversible ✘ No

Coalescence Droplets merge into larger ones → leads to ✘ Irreversible ✔ Yes

breaking

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Flocculation

●​ Flocculation happens when small droplets of the dispersed phase come together to form
clusters.
●​ It does not lead to droplet merging (coalescence) as long as the interfacial film remains
intact.
●​ Causes of Flocculation:
1.​ Low emulsifier concentration – If there is not enough emulsifier, droplets come
together easily.
2.​ Electrolytes (Salts) – Some salts reduce droplet repulsion, promoting flocculation.
3.​ High internal phase volume – More dispersed phase means droplets are packed
closely, increasing flocculation.
●​ Flocculation affects viscosity:
○​ More flocculation increases viscosity because droplets cannot move freely.
○​ Stirring reduces flocculation, lowering viscosity (shear thinning).

Creaming

●​ Creaming happens when dispersed droplets rise or settle due to gravity.

●​ If droplets remain separate, shaking can redisperse them.
●​ The Stokes equation explains creaming, but real emulsions have variations due to
different droplet sizes and interactions.
●​ Factors affecting creaming:
1.​ Droplet size – Larger droplets cream faster.
2.​ Density difference – If the densities of the two phases are similar, creaming is
reduced.
3.​ Viscosity – Higher viscosity of the continuous phase slows down creaming,
improving stability.

Coalescence (Breaking of the Emulsion)

●​ Coalescence occurs when emulsion droplets merge to form larger droplets.

●​ If this continues, the emulsion completely separates into two layers (breaks).
●​ How to prevent coalescence:
1.​ Use a strong interfacial barrier – Thick layers of emulsifier or solid particles
prevent droplet merging.
2.​ Nonionic surfactants and polymers – These stabilize emulsions by forming
strong protective films around droplets.
3.​ Natural gums and proteins – These can act as emulsifiers to prevent coalescence
at low concentrations and even work as primary emulsifiers at higher levels.

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Assessment of Emulsion Shelf-Life

●​ To evaluate physical, chemical, and functional stability of emulsions over time under
various stress conditions.
●​ Used to predict shelf-life and ensure product quality during storage.

Factors Affecting Shelf-Life

Packaging & Container Interactions

●​ ⚠️
⚠️ Leaching: Container extracts plasticizers or other components into emulsion
●​
●​ ⚠️ Loss of volatiles: Water or oil may evaporate via closures → destabilization
Absorption: Drug/emulsifier loss by absorption into container wall

Stress Testing Conditions

A. Aging & Temperature Cycling

●​ Standard test: Cycle between 4°C ↔ 45°C

●​ Detects:​
• Creaming​
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 • Coalescence​
• Viscosity shifts
●​ Freezing danger: Ice crystal formation + emulsifier insolubility → emulsion breakdown

B. Centrifugation

●​ Mimics long-term gravitational separation

●​ 🚫
●​ Standard: 3,750 rpm × 5 hrs ≈ 1 year of storage
>25,000 rpm: Causes artificial separation

C. Agitation

●​ Mild shaking: simulates transport & handling

●​ Excessive agitation: may induce coalescence​
(e.g., butter from cream under heavy churning)

Chemical Stability Considerations

Compound Stability Risk

PEG-based emulsifiers Oxidation → foul odor & degradation products
Non-ionic esters Hydrolysis in aqueous environment → ↓ emulsifying power

Physical Stability Parameters

1. Phase Separation

●​ Distinguish:
○​ Creaming = Reversible
○​ Coalescence = Irreversible
●​ Evaluate by sampling top, middle, bottom layers

2. Viscosity Changes

●​ O/W Emulsions: ↑ Viscosity due to flocculation

●​ ⚠️
●​ W/O Emulsions: ↓ Viscosity initially
Non-linear changes suggest instability

3. Electrophoretic Properties

●​ Zeta Potential: Indicates surface charge stability​

(↓ zeta potential = ↑ flocculation risk)
●​ Conductivity Changes: Signal aggregation or phase leakage

4. Particle Size Monitoring

●​ ↑ in droplet size = early sign of coalescence

●​ Use light scattering or microscopy for routine checks.
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