Colloids and suspensions

What type of free energy does a system favour?

Lowest free energy = least interaction between 2 phases = least shared SA

What is a disperse system? What are the 2 phases?

2 or more components in a heterogeneous mixture

Disperse and Continuous phase

What is a formulation with a liquid dispersed and liquid continuous phase?

Emulsion

What is a formulation with a solid dispersed and solid continuous phase?

Suppositories

What size are colloidal dispersions?

Particles 1nm-1μm in diameter

Not visible to naked eye

How to tell difference between colloid dispersion and solution? What is the effect called?

Dispersion will scatter light = illuminating path of beam of light

Tyndall effect

Difference between colloidal and coarse dispersions?

Colloidal suspensions have smaller particles (<1μm diameter) so gravity does not exert enough of an effect on them to cause settling

How do particles move in colloidal dispersions?

Brownian motion to diffuse within continuous phase

How can colloidal dispersions be separated?

Ultracentrifugation

Examples of daily colloidal dispersions?

milk, printing ink, blood

(plasma proteins rather than RBCs which will settle with time- erythrocyte sedimentation rate [ESR] test)

What is a suspension? How big are particels?

a coarse dispersion

Particles >1μm in diameter

What is the effect of gravitational forces on coarse dispersions/suspensions?

Larger particles (>1μm diameter) so gravity causes then to settle upon standing

How does the speed of sedimentation affect dosing?

Must be slow enough that a homogeneous dose can be obtained (poured/drawn into syringe) following shaking before settling again

May take some patients longer to dose e.g. arthritis

Can suspensions be delivered parenterally? Why?

Not usually as capillary diameter is 8-10μm so if particles (>1μm diameter) clump together they can be too large to enter caps

Advantages of dispersed systems (degradation, absorption x2, adsorption, taste)

Drugs susceptible to aqueous degradation may be formulated as a suspension

Increased absorption speed compared to solid oral dosage forms due to small particle size – slower than solutions though

Particle size can be tailored to optimise absorption rates

Active has high SA which can be used for adsorption (e.g. kaolin used for adsorption of toxins in GI tract for food poising)

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

Disadvantages of dispersed systems (liquids: stability, packaging; dosing)

As for all liquid formulations:

Active/excipient stability problems in presence of liquid

Liquids (esp. aqueous) are susceptible to microbial contamination

Administration of the correct dose can be less precise – settling, may take some patients longer to pour medicines (e.g. elderly with arthritis)

Size/weight/packaging issues for liquid formulations

More difficult to mask the taste of a drug in a liquid than solid formulation (although it is easier in a suspension than a solution) 

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

How does particle size affect taste of drugs?

Particles > 10μm cannot enter taste bud pore so particles in suspension have little taste (even less in solid formulations) compared to suspensions

But usually all oral formulations require excipients to improve taste - sweeteners, flavourings

What are the ideal properties of a dispersed system?

Particles should be evenly distributed in the continuous phase

Particles must not settle/sediment too rapidly

Sediment must be easily re-dispersed

Must easily flow out of the container

Particle size should be both small and uniform

What is a lyophobic colloid? What does this cause?

Solvent ‘hating’ system

Particles have different characteristics to dispersant = little attraction to dispersant = thermodynamically unstable = colloidal particles will aggregate to lower surface energy

Examples of lyophobic colloids in water?

water insoluble drugs, clays, oils, inorganic particles

What is a lyophilic colloid? What does this cause?

Solvent ‘loving’ system

Particles have an affinity for the dispersant = particles interact with dispersant molecules = causes solvation (called hydration in water) = prevents coagulation = inherently stable dispersion

Examples of lyophilic colloids in water

starch

gums - acacia, tragacanth

What is an amphiphilic colloids

Molecules with regions of different affinities to continuous phase

Orientate so each part of molecule is in contact with preferred phase

How do molecules arrange in amphiphilic colloids?

Start by arranging at the surface of the continuous phase until reaching critical micelle concentration (conc at which no space left at surface)

Then amphiphiles form spherical structures called micelles in continuous phase to remain orientated to preferred phase

What is the critical micelle concentration?

Conc at which no space left for molecules at surface of continuous phase

Above this micelles will form

What are liposomes? advantages? examples?

Bilayer structure of amphiphiles

Have a ‘pocket’ of continuous phase within them which can be used to encapsulate lyophilic materials to control delivery - protect them from enzymatic degradation, can control delivery time

e.g. mRNA vaccine delivery systems (as mRNA unstable in body as body breaks down foreign/unprotected genetic material)

How can lyophobic drugs be ‘solubilised’ using amphiphilic molecules?

Lyophobic drugs can be dissolved within the middle of the micelle or the bilayer of the liposome – this is a means of utilising colloidal systems to ‘solubilise’ poorly soluble drugs

So they are protected from enzymatic degradation and delivery time is controlled

What are association colloids?

Micelles and liposomes

As while they are sort of colloidal systems they are not static structures

The amphiphilic building blocks constantly disassociate and reassociate with one another to form new structures

What are nanoparticles?

Colloidal systems with permanent solid structures as the dispersed phase that are 1-100nm

What 4 factors of nanoparticles can be changed to maximise usefulness?

Size can affect where on body drug acts

Surface by attaching molecules/fgs/charges

Shape

Material nanoparticles are made of

What size particles in colloids bend light more?

Smaller particles bend light more = higher degree of light scattering

What is the Tyndall effect? What are the results in solution, colloids and suspensions?

Shine beam of light through:

Solution = no beam visible

Colloid = scattering of light causes beam path to be illuminated

Suspensions = scattering of light causes beam path to be illuminated and individual particles to be seen

What degree of light scattering do different colour wavelengths have?

Long wavelength (red) = least scattered

Short wavelength (blue) = most scattered/bent

How can particle size in a dispersion be measured?

Using light scattering property:

1. A laser diffraction particle size analyser shines a beam of laser light onto particles in a single file stream (passed in a narrow tube)

2. A detector measures the amount of deflection of the light and from this calculates the size of a particle

3. Over time, the distribution of sizes amongst all of the particles in a sample are measured

Why aren’t all suspensions colloids?

Difficult to generate small enough particles

1. Surface energy causes them to flocculate (associate into larger clumps)

2. Wetting (solvation/hydration) of particles more difficult as air adsorbs to surface of smaller particle easier and will be more difficult to displace

What is wetting? what does it prevent (3)?

The solvation/hydration of a solid particle

Its ability to stay in contact with a liquid

First stage of making a suspension to prevent particles:

1. remaining on liquid surface

2. attaching to container

3. forming larger clumps = flocculation

Why are smaller particles more difficult to wet?

As have adsorbed layer of air around particles that is harder to displace

What type of solids need a wetting agent?

Indiffusible solids

As they show some hydrophobicity so are not easily wetted

What is the purpose of a wetting agent?

They decrease interfacial tension to allow wetting and help dispersion

What are the forces that exist between the molecules in each phase called?

Cohesive forces

What are the forces that exist between the two phases called?

Adhesive forces

Are cohesive or adhesive forces usually greater? What does this cause?

Cohesive forces (between molecules of same phase) are usually greater

Causing tension (imbalance of forces) at the interface

How is wettability determined?

The degree of wetting is determined by the difference between adhesive (different phases) and cohesive (same phase) forces?

What is the main type of wetting agent? How do they work? What does shaking do (2)?

Surface Active Agents (SAAs - detergents)

Hydrocarbon chains that are adsorbed to hydrophobic particle surfaces while polar groups enter the liquid and become hydrated.

Shaking causes:

1. excessive foaming - due to stabilisation of bubbles created when air is mixed into the system

2. deflocculation of the system

How can hydrophilic colloids be used as a wetting agent?

Used in combination with SAA to cause deflocculation

Coat the solid hydrophobic particles with a layer, giving the particle a hydrophilic character

How can solvents be used as wetting agents?

Water miscible solvents decrease interfacial tension by:

1. penetrating powder clumps

2. displacing air

What is the effect of gravity on Brownian motion?

Brownian motion keeps small particles moving in a colloidal dispersion but as the particles get bigger, the influence of gravity is greater

Particles >0.5 -1μm start to have more significant gravity and will start to settle to the bottom

What is the idea of stokes law?

Velocity of sedimentation:

decreases as liquid density increases

increases as particle radius/g/density difference increases

What is Ostwald ripening?

Small particles dissolving in solution at higher temperature

Dissolved particles will join onto surface of larger particles when temp decreases and saturation is reached

Causes small particles to shrink and disappear, while large particles grow

Leading to much larger particles that will settle more quickly

When does Ostwald ripening occur?

When suspensions have particles of different sizes

Why do larger particles sediment quicker?

More mass = higher acceleration due to gravity (g)

What measures can be taken to prevent Ostwald ripening when dispersed phase has borderline soulbitly?

Lower temperature

Antisolvents

pH change

Drug salts created that are poorly soluble in continuous phase

Does the abosulte density value of particle/vehicle affect sedimentation rate?

No

The density difference between the two phases is important

What are density modifiers used for? Examples?

Tend to increase density of continuous phase

To lessen density difference

Syrup, glycerol, propylene glycol

What is viscosity? in terms of intermolecular forces?

The internal friction of a fluid, produced by intermolecular forces within the liquid phase

What factors affect viscosity?

Molecular size

Molecular shape

Molecular chemistry

Molecular concentration

Temperature

How does molecular size affect viscosity?

Larger molecule = higher viscosity

How does molecular shape affect viscosity? How does branching affect viscosity?

Shape influences area over which intermolecular forces occur

More branched = less points of contact for IMF = less IMF = less viscous

How does molecular chemistry affect viscosity? How does polarity affect viscosity?

Polar molecules can form hydrogen bonds = creating resistance to movement = increasing viscosity

How does molecular concentration affect viscosity?

Higher conc = more interactions between molecules = higher viscosity

How does temperature affect viscosity?

increase temp = adding energy to system = more movement of molecules and breakage of intermolecular interactions = decreases viscosity

What is rheology?

The study of flow

shearing stress and rate of shear

What is the shearing stress of a liquid?

The force per unit area required to cause the liquid to flow is called the “shearing stress” (σ),

σ = F/A

What is the rate of shear of a liquid?

The difference in velocity (dv) between two planes of liquid a given distance apart (dx) is the “rate of shear” (γ)

γ = dv/dx

What is the main relationship between shear stress and rate of shear?

Directly proportional for Newtonian fluids

How does viscosity affect shear stress?

The higher the viscosity of a liquid,

The greater the force per unit area (shear stress)

required to produce a given flow rate

What is a Newtonian fluid?

Substances in which shear rate is directly proportional to shear stress

They continue to flow in the same way, regardless of the forces acting on them

Their behaviour is simple and predictable, they behave as expected when disturbed or agitated

When pushed or pulled, they move or change shape in proportion to the force applied

Is water a Newtonian fluid? Why?

Yes

continues to behave in same way regardless of how fast is stirred/mixed

it has a proportional increase to the force of flow

What is Stoke’s law formula?

What is dynamic viscosity of a Newtonian fluid?

shear stress/shear rate

(inverse of gradient)

What is a non-Newtonian substance?

Do not have a constant viscosity

Viscosity changes with the applied shear force

Properties change in response to movement and deformation

What is plastic flow? what suspensions is it seen in?

A minimum force beyond which the material flows (yield stress/value)

Seen in concentrated suspensions with flocculated particles and high viscosity continuous phases

(as won’t flow much initially until a greater force is applied because acting quite solid-like)

What is pseudoplastic flow? What type of suspension is it seen in?

Viscosity decreases with the rate of shear = “shear thinning” fluid

Seen in flocculated dispersions containing long, high molecular weight molecules

The more stirring, the thinner the liquid gets, the more it flows: in-plane alignment, facilitates easier slipping past each other

What is dilatant flow? what type of suspension is it seen in?

Viscosity increases with the rate of shear = “shear thickening” fluid

Dispersions containing a high concentration of small, deflocculated particles

The more stirring, the thicker the liquid: out of plane alignment/aggregation, preventing slipping

How does shear thinning happen at a molecular level (alignment)?

in-plane alignment, facilitates easier slipping past each other

How does shear thickening happen at a molecular level (alignment)?

out of plane alignment or aggregation, preventing slipping

What is thixotropy?

Reversible, time-dependent change in viscosity, in some non-Newtonian fluids

At rest, particles form loose 3D gel structure

Shear stress via shaking disrupts bonds = causes shear thinning

When applied stress stops, the downcurve is displaced to the left indicating the gel structure reforms, but not immediately

For a given shear stress (X) the shear rate is lower (thicker) on the upward curve than the downward curve (thinner)

In thixotropy, for a given shear stress, is the rate higher on the downcurve or upcurve?

Downcurve is to the left

Shear rate is higher on the downcurve

Meaning viscosity (stress/rate) is lower = it is thinner

When does rheology matter in manufacturing and patient considerations?

Manufacturing considerations:

Mixing, Passing through machinery, Pouring/packing bottles

Patient considerations:

Physical stability

Ease of use e.g. pouring / spreading / injecting

Safety e.g. consistent dosing

Is a more or less viscous liquid preferred in storage? What type of shear stress is storage?

Storage = low shear

High viscosity preferred to slow/reduce sedimentation

Is a more or less viscous liquid preferred when shaking? What type of shear stress is shaking? (shaking prior to dosing)

Shaking = high shear

Low viscosity preferred to redisperse particles

What is the preferred flow for suspensions?

Pseudoplastic flow (and thixotropic)

high viscosity at low stress, low viscosity at high stress

slower sedimentation, faster redispersion

low gradient at low stress, high grad at high stress

Give examples of viscosity modifiers

polysaccharides, water-soluble celluloses, hydrated silicates, carboxypolymethylene, colloidal silicon dioxide

What are some pros/cons of natural products vs synthetic excipients?

Natural products are cheaper

Natural products suffer more from batch-batch variation

natural products are more of a risk factor for spore/microbial contamination so need more preservatives or shorter shelf-life

How are polysaccharides used as viscosity modifiers? examples? pros/cons (uses, pH, natural/synthetic/efficacy)?

Tragacanth, alginates, acacia gum, xanthan gum (Keltrol), starch

They form viscous thixotropic, pseudoplastic preparations

Can be used internally or externally - but sometimes feel too sticky topically

Narrow pH stability range

Mainly natural products: short-shelf life/contamination, batch-batch variation

Acacia and starch are not viscous enough alone so often combination with tragacanth

How are water-soluble celluloses used as viscosity modifiers? examples? pros/cons (viscosity, pH, natural/synthetic, efficacy)?

sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, microcrystalline cellulose

Semisynthetic polysaccharides (form viscous thixotropic, pseudoplastic preparations) with varying chain lengths

Longer chains = increased viscosity

Stable over wide pH range (unlike psc)

Some are non-ionic so suitable for use with ionic additives

Semisynthetic: less batch-batch variation, less contamination, more expensive

As more viscous than polysaccharides most are suitable to be used alone, combination not needed unlike acacia and starch psc

How are hydrated silicates used as viscosity modifiers? examples? pros/cons (uses, pH, natural/synthetic, efficacy)?

bentonite, hectorite, magnesium, aluminium silicate (Veegum)

Clays mined from ground = natural product

Used for both internal and external medicines (despite source)

Readily absorb up to 12x own mass of water = form thixotropic gels

natural products: cheaper, short-shelf life/contamination, batch-batch variation

How is carboxypolymethylene used as a viscosity modifer? pros/cons (uses, synthetic/natural, pH)

Synthetic polymer: less batch-batch variation, less contamination, more expensive

External use

Forms high viscosity products between pH 6-11 (alkaline) - very thin outside range

How is colloidal silicon dioxide used as a viscosity modifier? pros/cons (suspension use, synthetic/natural)

Synthetic: less batch-batch variation, less contamination

Aggregates in water to form 3D network (thixotropic)

Can be used in non-aq suspension

What is dynamic viscosity? units?

For a Newtonian liquid, the rate of flow (shear, γ) is directly proportional to the applied force (stress, σ)

The coefficient that describes the relationship is the dynamic viscosity (η):

σ = force / area = N/m² (or Nm^-2, or Pascal [Pa])

γ = change in velocity / change in distance

       = ms^-1/m which cancels to s^-1

η = σ / γ

η = Nm^-2/s^-1 (or Nm^-2s, or Pa.s)

What is kinematic viscosity? units?

Relates a liquid’s viscosity to its inertial force – inertial force is equivalent to density (ρ)

ρ = mass (kg) / volume (m³)

(note: 1 m³ = 1000 litres)

The coefficient that describes the relationship between dynamic viscosity (η) and density/inertial force (ρ) is kinematic viscosity (ν):

•ν = η / ρ = dynamic viscosity/density

•Units of ν are m²s^-1

(1 m²s^-1 = 1,000,000 mm²s^-1)

What are the 3 methods of measuring viscosity?

1. Capillary methods - how fast sample flows

2. Rotating methods - how hard it is to stir sample

3. Falling methods - how long it takes something to fall through sample

What are the 3 ways surfaces acquire an electrical charge when they come in contact with water?

1. Ion dissolution

2. Ionisation

3. Ion adsorption

How does ion dissolution affect surface charge?

Placing solid particles into water

More soluble ions dissolve into bulk of water

Leaving less soluble ions behind to create the particle surface charge

e.g. AgI:
Ag+ is more soluble in water so dissolves
Leaving I- ions behind so solid particle surface has a net negative charge

How does ionisation affect surface charge when pH is >/</= pKa?

Molecules at solid surface become ionised so particles acquire a surface charge

pH > pKa = negative charge particle surface - as alkaline solution takes cations, so cations are lost/anions are gained

pH < pKa = positive charge particle surface - as surface gains cations (e.g. H+ from acidic environment)

No net charge at isoelectric point = Zwitterion

What surface charge will ionisable particles have when pH > pKa?

negative

as alkaline solution so anions gained by particle

How does ion adsorption affect surface charge of particles? What is the usually surface charge of particles in water?

A surface charge can be acquired by the unequal adsorption of ions onto the surface

if more anions adsorb to a surface, the surface will develop a net negative charge.

Solid particle surfaces in water are more often negatively charged
because cations are generally more hydrated than anions
so cations tend to stay in the water phase
leaving the anions free to adsorb to the surface

This can involve OH^- / H₃O⁺ ions in water

How are ions distributed in dispersed systems? What is their charge if they have a surface charge?

A disperse system is overall electrically neutral and distribution of ions is uniform, but the surface charge of the particles influences the distribution of ions in the rest of the liquid

There is a layer around each particle with a different composition from the rest of system known as the electrical double layer and can be split into:

1. The inner region: includes the charged surface & adsorbed ions

2. The diffuse region: lies beyond adsorbed ions and up to the edge of the electrically neutral region

The electrically neutral region: outside the EDL (the bulk continuous phase)

What is the electrical double layer? What lies beyond it? stern and shear plane?

1. The inner region: includes the charged surface & adsorbed ions

   1. stern plane is within inner region, particles not free to move

   2. shear plane is between inner and diffuse region, beyond it particles move freely

2. The diffuse region: lies beyond adsorbed ions and up to the edge of the electrically neutral region

   1. initially opposite charged counterions, then some co-ions moving further away

The electrically neutral region: outside the EDL = the bulk continuous phase

What causes uneven distribution of ions in a disperse system?

the electrical double layer

some areas with more charge than others

potential = charge difference