Lesson 4A

Disperse system

Heterogeneous mixture of 2 or more components made up of a dispersed phase and a continuous phase

Dispersed phase

The phase that is broken up into particles or droplets

Continuous phase

The phase in which the dispersed phase is distributed

Monophasic system

A system with one phase, such as a true solution

Biphasic system

A system containing two distinct phases

Focus of this lesson

Disperse systems with a solid dispersed phase and a liquid continuous phase

Colloidal dispersion

Particles ~1 nm to 1 μm in diameter. Not visible to the naked eye (need electron microscopy) and do not settle under gravity. e.g. milk, printing ink, blood plasma proteins

Coarse dispersion (suspension)

Particles >1 μm in diameter. Liable to sedimentation under gravity so they settle on standing

How are colloids distinguished from solutions?

By the effect the dispersed phase has on light (Tyndall effect)

Why do colloidal particles not settle?

They are small enough that gravity has too little effect, and Brownian motion keeps them diffusing. They can only be separated by ultracentrifugation

Brownian motion

Random molecular motion that keeps very small colloidal particles suspended and diffusing

ESR test (erythrocyte sedimentation rate)

Measures settling of red blood cells in blood. RBCs settle with time but plasma proteins (colloidal) do not

Requirement for sedimentation in a suspension

Must be reversible by shaking (energy input) and slow enough that a homogeneous dose can be poured or drawn into a syringe

Why are suspensions unsuitable for some injections?

Capillary diameter is 8-10 μm so large particles are a problem. Particle size and material dictate delivery route

Advantage of disperse systems - stability

Drugs susceptible to aqueous degradation can be formulated as a suspension

Advantage of disperse systems - absorption

Faster absorption than solid oral dosage forms (small particle size) but slower than solutions. Particle size can be tailored to optimise absorption rate

Advantage of disperse systems - adsorption

Active has a high surface area that can be used for adsorption. e.g. kaolin adsorbs toxins in the GI tract

Advantage of disperse systems - flexibility

Allows flexibility of formulation e.g. taste masking of bitter drugs

Why do many drugs in solution taste foul?

Only individual drug molecules can interact with gustatory (taste) cells. e.g. quinine, a problem in children

Why do suspensions have little taste?

Particles >10 μm cannot enter the taste bud pore so particles in suspension have little taste

Excipients for oral formulations

Sweeteners and flavourings are generally required to improve taste and maximise compliance

Aspartame and taste

Artificial sweetener (dipeptide) that tastes sweet but its mirror-image enantiomer tastes bitter

Disadvantages of liquid formulations

Stability problems in liquid, microbial contamination (especially aqueous), less precise dosing, size/weight/packaging issues

Taste masking in liquids

More difficult than in solid formulations but easier in a suspension than a solution

Dosing risk with suspensions

If not shaken properly before each use accurate dosing cannot be assured

Properties of an ideal disperse system medicine

Evenly distributed particles, no rapid sedimentation, sediment easily re-dispersed, flows easily out of container, particle size small and uniform

Sol

Solid dispersed in liquid. e.g. starch in water, some inks, paints, milk of magnesia

Aerosol

Liquid dispersed in gas. e.g. clouds, fogs, mists, sprays

Emulsion

Liquid dispersed in liquid. e.g. milk, mayonnaise, butter

Gel

Liquid dispersed in solid. e.g. jellies, pearl, opal

Foam

Gas dispersed in liquid. e.g. whipped cream, beaten egg whites

Colloid classification

Based on the interaction between the dispersed and continuous phases: lyophobic, lyophilic, amphiphilic

Lyophobic colloid

Solvent "hating". Particles have little attraction for the dispersant, so the system is thermodynamically unstable and particles aggregate to lower surface energy. Needs careful formulation. e.g. water insoluble drugs, clays, oils, inorganic particles in water

Lyophilic colloid

Solvent "loving". Particles have affinity for the dispersant and become solvated (hydrated if water). This protective coat prevents coagulation so the dispersion is inherently stable. e.g. starch, acacia, tragacanth in water

Amphiphilic colloid

"Both loving". Molecules have regions with different affinities for the continuous phase so they orientate each part towards its preferred phase. e.g. sodium lauryl sulphate

Does a lyophilic colloid stay lyophilic in every dispersant?

No. A substance that is lyophilic in one dispersant (e.g. water) may not be in another (e.g. oil)

Critical micelle concentration (CMC)

Concentration at which amphiphiles have filled the surface of the continuous phase and start forming spherical micelles

Micelle

Spherical structure formed by amphiphiles above the CMC that keeps each part oriented to its preferred phase. Lyophobic drugs can be dissolved in the middle

Liposome

Bilayer-containing structure of amphiphiles (phospholipids and cholesterol) with a hydrophilic core. Hydrophobic drugs sit in the bilayer and hydrophilic drugs in the core. e.g. mRNA vaccine delivery, Doxil (FDA approved 1995)

Association colloids

Micelles and liposomes. Not static as the amphiphilic building blocks constantly dissociate and reassociate

Nanoparticles

Solid particles with permanent structure and size 1-100 nm. A type of colloidal system

Tyndall effect

Light shone through a colloid is scattered, illuminating the beam path (beam visible). In a solution the beam is invisible. In suspensions individual particles are also visible

Light scattering and particle size

Small particles bend light more than big particles

Light scattering and wavelength

Short wavelength (violet/blue) is scattered more than long wavelength (red). This is why the sky is blue

Laser diffraction particle size analyser

Laser beam hits particles in a single-file stream. A detector measures deflection of light and calculates particle size and size distribution

Why aren't all suspensions colloids?

Hard to make particles small enough (surface energy makes them clump) and air adsorbed on very small particles makes wetting difficult. So larger particles are more commonly used

Suspension

Formulation of insoluble solid particles (>1 μm) distributed throughout a liquid continuous phase. Usually aqueous but oily vehicles are sometimes used

Oily depot suspension

Antipsychotics or steroids in oil. Remain as oily globules after injection, reducing surface area in contact with physiological fluids and slowing absorption

Wetting

The ability of a solid particle to stay in contact with a liquid. Must be the first stage of making a suspension

What happens if particles are not wetted?

They stay on the liquid surface, attach to the container or form large clumps in the liquid

Diffusible solids

Easily wetted so straightforward to suspend in the aqueous phase

Indiffusible solids

Show some hydrophobicity so are not easily wetted and need a wetting agent

Why are finely divided substances hard to wet?

An adsorbed layer of air surrounds the particles

Wetting agents

Decrease interfacial tension to allow wetting and help dispersion

Cohesive forces

Forces between molecules within one phase

Adhesive forces

Forces between the two phases

Interfacial tension

Imbalance of forces at an interface because cohesive forces are greater than adhesive forces. Wettability depends on the difference between adhesive and cohesive forces

Surfactants/detergents as wetting agents

Surface active agents (SAAs). Hydrocarbon chains adsorb to hydrophobic particle surfaces while polar groups enter the liquid and are hydrated

Challenges of SAAs as wetting agents

Excessive foaming on shaking (stabilise air bubbles) and may cause deflocculation

Hydrophilic colloids as wetting agents

Coat hydrophobic particles with a layer that gives them hydrophilic character. Can be combined with SAAs but may also cause deflocculation

Solvents as wetting agents

Water miscible solvents decrease interfacial tension by penetrating powder clumps and displacing air

Sedimentation

Settling of dispersed particles under gravity. Significant for particles larger than about 0.5-1 μm

Stokes' Law

Velocity of sedimentation of a particle falling through a liquid: v = 2r²(ρs − ρl)g / 9η. Depends on particle radius, density difference, gravity and viscosity

Effect of particle radius on sedimentation

Larger particles settle faster (v is proportional to r²)

Why can flocculation help sedimentation behaviour?

Flocculating creates a larger effective particle size which, despite faster sedimentation, can give benefits in sedimentation behaviour

Ostwald ripening

Thermodynamic process where smaller particles dissolve and redeposit onto larger ones. Small particles get smaller and large get larger. Driven by long storage and temperature changes

Why does temperature drive Ostwald ripening?

Higher temperature increases solubility and smaller particles are more soluble. When temperature drops solubility falls and molecules deposit on larger particles

Reducing Ostwald ripening

Use actives with very low solubility in the continuous phase. For borderline solubility use antisolvents, pH adjustment or drug salts

Effect of density on sedimentation

It is the relative density difference between particle and vehicle that matters. e.g. cannonball in water vs mercury

Density modifiers

Lessen the density difference between phases. They tend to increase vehicle density. e.g. syrup, glycerol, propylene glycol

Viscosity

The resistance of a fluid to flow. Internal friction produced by intermolecular forces in the liquid phase. Symbol η (eta)

Factors influencing viscosity

Molecular size, molecular shape, molecular chemistry, molecular concentration, temperature

Viscosity and molecular size

Larger molecules tend to have higher viscosity than smaller ones. e.g. higher molecular weight PEGs

Viscosity and molecular shape

Shape affects area of intermolecular forces. A branched molecule acts like a smaller molecule than a straight chain of identical molecular weight

Viscosity and molecular chemistry

Polar molecules form hydrogen bonds which resist movement and increase viscosity. e.g. 1-pentanol more viscous than hexane

Viscosity and concentration

Higher concentration means more molecular interactions and higher viscosity

Viscosity and temperature

Increasing temperature decreases viscosity (more molecular movement and broken intermolecular interactions). e.g. warm vs cold honey

Rheology

The study of flow

Shear stress (σ)

Force per unit area required to cause a liquid to flow. σ = F/A. Units N/m² (Pa)

Rate of shear (γ)

Difference in velocity (dv) between two planes of liquid a given distance apart (dx). γ = dv/dx. Units s⁻¹

Newton's observation

Rate of flow (γ) is directly related to applied force (σ) via the constant η (viscosity). Higher viscosity needs greater force per unit area for a given flow rate

Newtonian flow

Shear rate is directly proportional to shear stress (linear relationship) with constant viscosity regardless of forces applied. e.g. water. Rare in pharmaceutical formulations

Non-Newtonian fluid

Does not have a constant viscosity. Viscosity changes with applied shear force giving non-linear behaviour

Plastic flow

Has a minimum force (yield stress/value) before the material flows. Seen in concentrated suspensions with flocculated particles and high viscosity continuous phases

Pseudoplastic flow

Viscosity decreases with rate of shear (shear thinning). Seen in flocculated dispersions with long, high molecular weight molecules

Dilatant flow

Viscosity increases with rate of shear (shear thickening). Seen in dispersions with a high concentration of small, deflocculated particles

Shear thinning at molecular level

Shear causes in-plane alignment so molecules slip past each other more easily

Shear thickening at molecular level

Shear causes out-of-plane alignment or aggregation which prevents slipping

Thixotropy

Reversible, time-dependent change in viscosity in some non-Newtonian fluids. At rest a loose 3D gel structure forms, shaking breaks it down (shear thinning) and it reforms after stress stops but not immediately

Thixotropy on a rheogram

Down curve is displaced to the left of the up curve. At a given shear stress the shear rate is lower (thicker) on the upward curve than the downward curve

Rheology - manufacturing considerations

Mixing, passing through machinery, pouring and packing bottles

Rheology - patient considerations

Physical stability, ease of use (pouring, spreading, injecting), safety (consistent dosing)

Ideal rheological behaviour of a suspension

High viscosity during storage (slows sedimentation, improves stability) and low viscosity during use (easy redispersion on shaking, easy pouring and accurate measurement