Pharmaceutical Suspensions

A Formulators Guide - Jim McElroy

◦ Suspensions are classified on the basis of the Dispersed Phase (DP) and the Dispersion Medium (DM).

◦ The former (DP) is essentially a solid while the latter (DM) may either be a solid, a liquid or a gas.

Suspensions

◦ USP defines suspensions as “finely divided, undissolved drugs dispersed in liquid vehicles.”

◦ The USP defines several suspension dosage forms that are historically referred to by other names. They are: Milks (flocculated suspensions) Gels *(structured vehicle) Lotions and Creams (emuslions)

*If the DP is soluble in the DM then this gel is not a suspension.

Definitions

Intermolecular Forces• Electrostatic Repulsive Force• Steric Repulsive Force• Van de Waals Force• Repulsive Hydration force

◦ Electrostatic Repulsive Force – charged particles exert a force on one another. e.g. Ionic molecules keep the particles apart

◦ Steric Repulsive Force – arises from the adsorption of large molecules. Can be controlled by formulation e.g. Sterically stabilized dispersions are stable when

the polymer is soluble.

Interparticle Forces That Can Be Controlled by Formulation

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Electrostatically Stabilized Sterically Stabilized

◦ Van de Waals Force - attractions between atoms, molecules, and surfaces. e.g. particles overcome the repulsion forces (possibly

due to Brownian motion or differential sedimentation rates, agglomerate and attract each other

◦ Repulsive Hydration Force – arises from the structuring of water in the interfacial region. Operates over short distances. e.g. it is controlled by the interdependcence of ionic

strength, surface charge density, particle size and surface dipole density

Interparticulate Forces That Cannot Be Controlled by Formulation

Colloid science has held that electrostatic and electrodynamic (van der waals) forces are principle determinants of colloid systems.

Interaction between two dipoles that are either permanent or induced. The temporary dipole and the induced dipoles are attracted to each other. It is always present, it is short-range, and it is attractive.

Van der Waals Forces

Hydration Repulsion is:◦ work needed to remove water molecules from

hydrophilic(water loving) surfaces at small film thicknesses and is described by an exponentially decaying interaction potential.

Repulsive Hydration Force

DLVO

Charge at the true surface

adsorbed counterions tightly bound and move with the solid

complete neutralization of the surface

charge

complete neutralization of the Nernst

potential

thickness of the double layer is inversely related to ionic strength and ion valence

SUSPENSION TYPES• Flocculated Suspension• Structured Vehicle• Emulsions

◦Particles finer than 0.1 µm in water remain continuously in motion due to electrostatic charge (often negative) which causes them to repel each other.

◦The distance between particles is approximately 100 to 200 A.

◦The network is easily disrupted by shaking but it reforms when the turbulence stops.

Flocculated Suspension

Rapid rate of sedimentation due to large size of floccules

Clear supernatant as all particles are incorporated into floccules

High sediment volume Sediment easily re-dispersed by shaking

Properties of Flocculated Suspensions

◦Adjust electrostatic repulsive force use an electrolyte

◦Modify the Nernst (equilibrium) potential reduce surface charge by adsorbing

anions to it◦Adjust steric repulsive force adsorb a neutral polymer

◦Heteroflocculation Add small oppositely charged particles

to produce a particle network

Formulation Considerations

Adjust or modify: the Nernst Potential using an ionic species

such as phosphate anions the electrostatic repulsive force by using an

electrolyte like sodium chloride The steric repulsive force adsorbing a

neutral polymer like polyvinyl alcohol

Examples:

◦Produce a liquid phase which exhibits shear thinning rheology, i.e. very viscous on the shelf to prevent settling and fluid when shaken.

◦Usually contains a polymer and a clay (or several polymers) in order to produce a shear-thinning system.

Structured Vehicle Suspension

◦May appear as a semi-solid when undisturbed

◦Fluid when shaken◦Thixatropic (becomes fluid when stirred

or shaken and returning to the semisolid state upon standing )

◦No sedimentation

Properties of Structured Vehicle Suspensions

Exhibited by polymer solutions. Increasing flow as the shear stress is increased. The viscosity decreases as the shear stress is increased.

Pseudoplastic Flow

Dilantant Flow

The system becomes more viscous as the shear stress is increased.

Note: Production equipment often introduce more shear than laboratory equipment.

◦Addition of “inert” small particles such as clays like montmorillonite or silica dioxide

◦Mixture of polymers and “inert” small particles like sodium carboxymethycellulose with montmorillonite or silica dioxide

◦Use of liquid-crystalline phases with surfactants at concentrations above the Critical Micelle Concentration (CMC).

Examples

A two phase system consisting of two incompletely immiscible liquids, one of which is dispersed as finite globules in the other.

The particle size of the globules range from 0.1 to 10 microns.

A surfactant system and (usually) mechanical energy are needed to join the phases.

Emulsions

Emulsions Are Thermodynamically Unstable.

All emulsions eventually coalesce to reduce the total free energy of the system…

the emulsion “breaks”

Emulsion TYPES• Oil-in Water• Water-in-Oil

Typical Pharma Emulsions

Predicting O/W or W/O Emulsion Important parameters include:

◦ Choice of emulsifiers◦ Phase-Volume Ratio◦ Method of Manufacture◦ Temperature (processing and storage)

The better the emulsifying system the less important the other factors

Common Surfactants Anionic - hydrophilic group has an anionic charge e.g.

soaps, shampoo, detergents Cationic - have a cationic charge e.g. preservatives,

conditioners Nonionic - no charge e.g. food additives Amphoteric - contains two oppositely charged groups e.g.

lysergic acid, psilocybin Finely Divided Solids – e.g. clays, bentonite (called a

Pickering Emulsion) Proteins - e.g. casein, egg yolks Naturally Occurring – e.g. lanolin, lecithin, acacia,

carrageen and alginates

Free Energy

· Molecules at an interface will align in the easiest transition between two bulk phases. In a solution of water , surfactant molecules

align so that its polar groups are immersed in water and its chains are sticking out into the air phase

In an oil/water dispersion, surfactant molecules align so that its polar groups are immersed in water and its chains are sticking out into the oil phase

Droplet Size Distribution

Emulsions change their size distributions over time with the average droplet size shifting to larger values

A sharply defined distribution containing a the maximum fraction of small-diameter droplets is usually more stable

Rheology

Continuous Phase: O/W emulsion can be partially controlled by clays and gums W/O emulsion by the addition of high-melting waxes and polyvalent metal soaps

Internal Phase: No impact to final emulsion viscosity

Droplet Size & Distribution: The viscosity of emulsions having similar size distributions about a mean diameter is inversely proportional to the mean diameter

Processing

Method of Preparation◦Order of addition◦Rate of addition◦Energy effects

Order of Addition

Placement of surfactants: Ideally, lipophilic surfactant should be dispersed

in the oil phase. Finer emulsions result when the hydrophilic surfactant is also dispersed in the oil phase.

Oil to water or water to oil: If processing permits, addition of aqueous to the

oil phase produces the finest emulsions. If the oil phase is added to the aqueous phase,

more energy will be required to produce small droplets.

Rate of Addition A significant improvement in the emulsion can

sometimes be seen by adding the aqueous phase at a slower rate.

Energy Effects (Processing) Emulsions can be sensitive to energy input

or energy removal from the system Cooling rate can impact the system Mechanical or heat energy will not

overcome systemic problems with a formula

Temperature Effects/Shelf Life Temperature can affect:

◦The rheology of the system◦The HLB of the emulsifiers◦The ability of the emulsifier to adsorb or

desorb from the droplet interface◦The mechanical strength and the

elasticity of the interfacial film.

Pickering Emulsion

It is an emulsion that is stabilized by solid particles (for example colloidal silica) which adsorb onto the interface between the two phases.

Generally the phase that preferentially wets the particle will be the continuous phase in the emulsion system.

Sunscreens fall typically into this category

Micro Emulsions

Oil, water and surfactants High concentration of surfactant relative to

the oil (~50%) System is optically clear fluid or gel Phases do not separate on centrifugation System forms spontaneously

Suspensions are a preferred and widely accepted pharmaceutical dosage form.

Creating a stable formula that is efficacious requires some knowledge about the basic physics of the suspension/emulsion to be deployed

Ingredients are key

Conclusion