7_Suspensioner og emulsioner 1

Introduction to Formulation and Production of Pharmaceuticals

• Topic: Suspensioner og emulsioner

• Lecturer: Judith Kuntsche

• Date: 23/10-2024

• Course Code: FA 511

• Semester: Fall 2024

Composition and Typical Auxiliary Groups

• Disperse Phase:

  • Solid particles (in suspensions)

  • Emulsion droplets (in emulsions)

• Dispersion Medium:

  • Water and other hydrophilic liquids

  • Lipophilic liquids (e.g., vegetable oils)

• Stabilizers:

  • Surfactants (surface-active agents)

  • Electrolytes (especially in suspensions)

  • Viscosity-increasing agents (thickeners)

  • Substances that increase the density of the dispersion medium (especially for suspensions)

• Additional Auxiliary Groups:

  • Preservatives

  • Antioxidants

  • Flavorings, sweeteners, and colorants (oral suspensions and emulsions)

Overview of Disperse Systems

• Definitions

• Stabilization of suspensions and emulsions

• DLVO Theory

• Electrostatic and steric stabilization

• Role in pharmaceutical formulations

Solutions, Colloids, and Macroscopic Dispersions

• Properties:

  • Solutions (molecularly dispersed): < 1 nm

  • Colloids: 1 nm – 500 (1000) nm

  • Macroscopic dispersions: > 1 µm

• Visualization Techniques:

  • Solutions: ---

  • Colloids: Electron microscopy

  • Macroscopic dispersions: Light microscopy

  • Separation Techniques:

    • Reverse osmosis

    • Dialysis

    • Ultrafiltration

    • Ordinary filtration (filter paper)

• Examples:

  • NaCl solution

  • Glucose solution

  • Polymer solutions

  • Micelles, nanoparticles

  • Macroscopic emulsions and suspensions

Colloids

• Colloid Types:

  • Lyophilic colloids: High affinity for the dispersion medium (solvent-loving)

    • Example: Polymer solutions

  • Associative colloids: Self-aggregation of amphiphilic molecules (micelles)

  • Lyophobic colloids: Low or no affinity for the dispersion medium (solvent-hating)

    • Example: Parenteral fat emulsions

• Size in the nm range

Size Dimensions

• Comparison of particle sizes:

  • d ~ 22 cm (soccer ball)

  • d ~ 80 μm (hair)

  • d ~ 150 nm (virus capsid)

• Scale Reference:

  • 1 m, 1 mm, 1 μm, 1 nm, 0.001 m, 0.000'001 m, 0.000'000'001 m

  • d ~ 2.5 cm (flea)

  • d ~ 7 km (erythrocytes)

  • Diameter of chain ~ 2 nm (DNA chain)

  • Source: Ziegler, Medizinische Monatszeitschrift 12, 455 (2008).

Definitions

• Disperse Systems:

  • Consist of at least two phases, where one phase (disperse phase, inner phase) is finely distributed in the other phase (dispersion medium, outer phase, continuous phase).

  • Types:

    • Polydispersed

    • Monodispersed

    • Incoherent (separated)

    • Coherent (interconnected)

Overview of Disperse Systems by Physical State

• Examples of Systems:

  • Disperse Phase / Dispersion Medium

  • Solid/Fast / Solid

  • Suspension

  • Liquid/Fast / Solid

  • Emulsion

  • Gas/Liquid / Foam

  • Solid/Gas / Smoke

  • Liquid/Gas / Fog

Suspensions and Emulsions

• Suspensions:

  • Disperse systems where the disperse phase consists of solid particles finely distributed in the outer phase (dispersion medium).

• Emulsions:

  • Disperse systems containing two (or more) immiscible liquid phases, where the disperse (inner) phase is finely distributed in the dispersion medium.

Relationship Between Particle Size and Surface Area

• General Concept:

  • Suspensions and emulsions are thermodynamically unstable systems (tendency to reduce surface or interfacial area).

• Table of particle size, number of particles, specific surface area, surface energy:

  • 1 cm, 1, 6, 0.02287

  • 1 mm, 103, 60, 0.2287

  • 100 µm, 106, 600, 2.287

  • 10 µm, 109, 6’000, 22.87

  • 1 µm, 1012, 60’000, 228.7

  • 100 nm, 1015, 600’000, 2’287

Example: Emulsion

• Concept:

  • Dispersion of oil in water forms an emulsion.

  • Emulsions are thermodynamically unstable; oil droplets coalesce and grow larger over time, leading to complete phase separation (thermodynamic stability).

  • Factors: Free energy of the interface, interfacial area, interfacial tension.

Stabilization of Suspensions and Emulsions

• Key Concepts:

  • Unstabilized systems have reduced interfacial tension and a kinetic barrier (activation energy).

  • Suspensions and emulsions must be stabilized with suitable auxiliary materials.

DLVO Theory (Deryagin, Landau, Verwey, Overbeek)

• Interaction Energy:

  • Total interaction energy between two particles is the sum of attractive potential energy and electrostatic repulsive energy.

  • Repulsive forces arise from electrical charges on the particle surface, while attractive forces stem from van der Waals forces between particles of the same type.

Electrical Properties at the Interface

• Components:

  • Electric double layer, particle surface, glide plane, specific adsorbed ions, Stern plane, and zeta potential.

Effect of Electrolytes

• Observation:

  • Zeta potential (nominal value) decreases with increasing electrolyte concentration because more ions are available to shield the particle's surface charge.

Example: Parenteral Fat Emulsion (Intralipid)

• Observation:

  • Zeta potential depends on salt concentration; flocculation is the first sign that the emulsion is being destabilized.

Steric Stabilization

• Concept:

  • Steric interaction of particles with adsorbed polymers on the particle surface reduces the movement freedom of polymer chains, thus stabilizing the system.

Electrostatic vs. Steric Stabilization

• Comparison:

  • Assess the repulsive and attractive interactions between particles and how they affect the stability of dispersions.

Importance of Suspensions and Emulsions

• Applications:

  • Formulation of poorly water-soluble drugs (emulsions for solubilization)

  • Taste masking (many drugs have bad flavor)

  • Depot formulations (e.g., IM/SC lipophilic injection fluids)

  • Convenience for administration (oral use)

• Advantages and Disadvantages:

  • Physical instability

  • Development and production (large scale) not easy

  • Aesthetic considerations (reversible instability)

  • Space-consuming (transport and storage)

  • There is no specific monograph for suspensions and emulsions in Ph.Eur., but they are included in various other monographs.

Summary of Important Points

• Key Definitions:

  • Colloids

  • Disperse systems

  • Suspensions

  • Emulsions

• Stabilization Mechanisms:

  • Interfacial energy

  • Electrostatic and steric stabilization

  • Zeta potential

  • DLVO plot

• Roles in Pharmaceutical Formulation:

  • Advantages and disadvantages

• Important Auxiliary Groups:

  • Preservatives, antioxidants, flavoring agents, etc.