Colloids + Suspensions

What is a dispersed system

• A system in which one component is dispersed as particles OR droplets (dispersed phase) throughout another component (continuous phase)

• 2 phase system (compared to solutions which only have 1 phase)

• E.g. colloids, suspensions, emulsions

Compare a dispersed system to a solution

• Dispersed systems have 2 phases, solutions have 1 phase

• Disperses systems consist of particles or droplets, solutions consist of molecules

What is a liquid in gas dispersion called?

Liquid aerosol e.g. cloud

What is a solid in gas dispersion called?

Solid aerosol e.g. smoke

What is a gas in liquid dispersion called?

Foam e.g. Bath foam

What is a liquid in liquid dispersion called?

Emulsion e.g. milk

What is a solid in liquid dispersion called?

Suspension e.g. calamine lotion

What is a liquid in solid dispersion called?

Solid emulsion e.g. ice cream

Define colloidal dispersions

• Dispersions in which the size of the dispersed particles in the continuous phase is in the range of 10^-9 - 10^-6m

Suppose we add a powder of drug to water. How do I know if I have a colloid or solution?

• In a solution, the drug molecules will be dispersed on a molecular scale in the solution - each molecule is separate from another

• In a colloid, we have particles of a drug - aggregates of many drug molecules

What is the difference between a pharmaceutical suspension and a colloidal system?

• In a pharmaceutical suspension, particle size is > 1um

• In a colloid, the particle size is < 1um

Why do we use suspensions?

• Poorly soluble drugs cannot always be made into solutions

• For taste masking - unpleasant tastes may be less noticeable in a suspension than solution

• Drug may be more stable if formulated as a suspension instead of solution

  » many drugs are esters and can hydrolyse easily if in a solution

  » as a suspension, most of the drug molecules are in the middle of a larger particle so water can’t reach them = less likely to be degraded

• Drug may be more stable as a solid, so the suspension is made just before dispensing

Examples of OTC suspensions

• Calamine lotion

  » Applied topically

  » Treats minor rashes / irritation on the skin

• Kaolin mixture BP

  » Administered orally

  » Treats mild diarrhoea

Example of prescription suspensions

• Nyastatin suspension

  » Administered orally

  » Treats fungal infections in mouth, throat, intestines

• Betoptic

  » Ophthalmic administration

  » Reduces pressure in the eyeball

What makes a good suspension?

1. The suspension must be easy to disperse upon shaking » redispersibility

   » A fresh suspension is made consisting of solid + liquid

   » Over time the particles will sink to the bottom as particles are more dense than water

   » Upon shaking, the particles should become evenly distributed (homogenous)

2. The suspension should contain particles which are small and of the same size

   » Ensures patients do not find it gritty

3. The suspension must be homogenous

   » After shaking and removing the dose, the particles must be evenly distributed throughout the liquid

   » Ensures there is an equal concentration of drug throughout the suspension

   » So the patient gets the same dose every time

Optical properties (effect of light) of colloids + suspensions

What happens when light passes through a true solution?

What happens when light passes through a colloid / suspension?

• If a beam of light passed through a true solution, there is very little scattering of the light, so the path of the beam cannot be seen

• If a beam of light is passed through a colloid/suspension, the particles scatter the beam of light so you can see its path

Optical properties (effect of light) of colloids + suspensions

Label the journey of light through a colloid / suspension

Optical properties (effect of light) of colloids + suspensions

What is the Tyndall effect?

• Allows colloidal systems / suspensions to be assessed based on how a beam of light behaves when it comes into contact with the system

• Light scattering makes colloidal systems look cloudy or turbid

• Turbidity is given by:

  I = I₀e^-tL OR ln(I / I₀) = -tL

  Transmitted light = Incident light x exponential function^{-turbidity x path length}

• The less light that passes through the sample = the more turbid it is = the greater concentration of the dispersed phase (as more particles are scattering the light)

Optical properties (effect of light) of colloids + suspensions

Why is I (transmitted light) always less than I₀ (incident light)

• Light is scattered by particles in the colloid/suspension

• So less light exits the suspension than entered it

Motion in colloids

What kind of motion do the particles undergo?

• The particles are small <1um

• This means they undergo brownian motion » random movements of the particles in an irregular and zig zag pattern

• This is due to random collisions with the solvent molecules, other particles and the container wall

Diffusion in colloids + suspensions

How do the particles diffuse?

How can we calculate factors affecting diffusion?

• Particles diffuse from high concentration to low concentration

• This means we don’t have to be careful about evenly distributing the solid when making the suspension

• Fick’s first law:

  dm / dt = -DA x dC/dx

  dm/dt = mass diffusing / time

  D = diffusion coefficient

  A= area across which diffusion occurs

  x = distance travelled

  dC/dx = concentration gradient

Sedimentation in colloids + suspensions

How do we calculate the velocity of sedimentation of solid particles in a suspension?

Stokes’ Law:

V = 2a²g(σ - ρ) / 9η

a = radius of the solid particles

σ = density of the solid

ρ = density of the liquid

η = viscosity of the liquid

g = acceleration due to gravity (9.8)

Sedimentation in colloids + suspensions

How do you calculate the sediment ratio

R = height of sedimented layer (h) / initial height of suspension (h₀)

Sedimentation in colloids + suspensions

Why does sediment ratio (R) always start at 1?

As at the start, the drug is evenly distributed throughout the suspension

Sedimentation in colloids + suspensions

What happens to sediment ratio over time?

• Overtime, there is more sedimentation

• So h (height of sedimented layer) gets smaller as the layer of sedimented solid becomes denser

• So h / h₀ decreases

• So sediment ratio decreases over time

• A low sediment ratio = caking

Sedimentation in colloids + suspensions

What can sedimentation of the solid particles lead to?

• Caking

• Sedimentation can lead to a very dense, non-dispersible aggregate at the bottom of the container

• This solid cannot be redispered upon shaking = undesirable for a suspension

How do we make a pharmaceutical suspension?

1. Drug must have small particles of uniform size

2. If the drug is water-insoluble, add a wetting agent. This breaks the interfacial tension, ensuring the solid particles disperse easily throughout the liquid

What is interfacial tension?

• The energy barrier which prevents the liquid spreading around the solid

• If the drug and solvent are hydrophilic = low interfacial tension = liquid spreads around the particles = good suspension

• If drug is hydrophobic = high interfacial tension = liquid does not spread around the particle = bad suspension

Wetting agents

What do wetting agents do?

• Breaks the interfacial tension, allowing the solid particles to disperse easily throughout the liquid

Wetting agents

Types of wetting agents

• Surfactants » have a hydrophilic head and hydrophobic tail

• Hydrophobic colloids

• Simple solvents e.g. alcohol, glycerol

Wetting agents

How do wetting agents cause particles to disperse throughout the liquid?

• Hydrophobic drug particles will stick together. This is called clumping

• Wetting of the drug leads to a decrease in surface tension

• This prevents the particles from clumping and causes them to disperse throughout the liquid

• Hydrophobic drug particles also tend to cling to the container to be as far away as possible from the hydrophilic solvent

• Wetting agents decrease adsorption of particles to the container by applying a repellant coating to the particles

Wetting agents

Describe how a surfactant can be used as a wetting agent

• The hydrophobic tails stick to the hydrophobic drug particle

• The hydrophilic heads are on the outside

• So water can spread around the drug particle to form a suspension

What 2 types of suspensions can we have?

1. Deflocculaed

2. Flocculated

Deflocculated suspension

What is it?

How does the suspension look?

What is the sedimentation like?

Good or bad?

• The particles remain as separate units

• Suspension remains cloudy for a prolonged period of time

• Small volume of final sediment

• Rate of sedimentation is slow

  » This prevents liquid from being trapped in the sediment

  » So the sediment becomes compact, causing caking

  » Difficult to redisperse = bad suspension

Flocculated suspension

What is it?

How does the suspension look?

What is the sedimentation like?

Good or bad?

• The particles exist as loose aggregates

• Suspension clears quickly

• Large volume of final sediment

• Rate of sedimentation is rapid as the aggregates are heavier

  » This leads to liquid entrapment within the sediment

  » So easy to redisperse = good suspension

Compare a flocculated and deflocculated suspension

Draw a graph to show how the sediment ratio differs in a flocculated and deflocculated suspension

Draw a diagram showing how the different states of a suspension arise

What is the difference between flocculation and coagulation in a suspension?

Coagulation:

• Arises when the particles are closely aggregated and difficult to redisperse

• Strong forces holding the particles together

• Leads to caking

Flocculation:

• The aggregates have a loose structure in which the particles are a small distance apart

• The particles are only weakly bound together

What is caking?

• The formation of a densely packed, non-dispersible, aggregate at the bottom of the container in a suspension

• This means that the drug is not evenly distributed throughout the suspension

• Which can lead to the patient underdosing and then overdosing (as all the drug is at the bottom)

How can we delay sedimentation and caking?

Viscosity enhancing agents

• V = 2a²g(σ - ρ) / 9η

• So if we increase viscosity of the liquid phase (η), the rate of sedimentation is reduced

E.g. polysaccharides, celluloses (presence of polymers makes a suspension thicker)

E.g. hydrated silicates, carbomers and silicon dioxide

NOTE: This only DELAYS sedimentation. It does not STOP it, so caking will still happen eventually

Draw a graph to show how the sediment ratio changes when a viscosity enhancing agent is added to a syspension

How can we prevent caking?

By using flocculating agents

Flocculating agents

How do flocculating agents prevent caking?

• Encourages the formation of flocs

• These are loosely bound aggregates which sink quickly

• This means they have no time to pack together tightly

• So there is liquid trapped between the particles

• So the particles can be dispersed easily

Flocculating agents

Ideally, how flocculated do we want the system to be?

Partially deflocculated

Too deflocculated = caking

Too flocculated = sinks too quickly before patient can take medicine

Flocculating agents

Examples

• Electrolytes AKA salts (sodium acetate, phosphate, citrate)

• Surfactants (ionic or non-ionic)

• Polymers (starch, cellulose, alginates)

• Carbomers or silicates

Electrical properties of particles in colloids and suspensions

• Particles have a surface charge

• In water, this is typically negative e.g. COOH will deprotonate to form COO-

• The negative charge at the particle surface will attract positive ions in solution

• These will then attract negative ions

• This forms an electrical double layer

How do all the forces in a colloid/suspension work?

• All the particles in a suspension are made of the same drug so have the same charge » these particles repel each other (V_R)

• There are also some attractive forces (V_A) from Van der Waals forces between the molecules

  • Permanent dipole - permanent dipole interactions

  • Permanent dipole - induced dipole interactions

  • Temporary dipole - induced dipole forces

Flocculating agents

What theory does flocculation depend on?

DVLO theory:

V_T = V_A + V_R

V_T = total potential energy of interaction

V_A = potential energy of attraction (VDW forces between molecules)

V_R = potential energy of repulsion (repulsion between particles)

Explaining DVLO Theory

Stern layer

Potential

• There is a negative charge at the surface of the particle

• So positive counter ions in solution will be attracted to the surface of these particles very strongly.

• These are tightly attached and don’t move

• This is called the stern layer

• Potential shows the charge between 2 adjacent particles

• When particles are close together = more repulsion = more potential

Explaining DVLO Theory

Shear plane

• Double layer of the particle surface consisting of the inner layer (stern layer) and outer layer (diffuse layer)

Inner layer (stern layer):

• Ions are tightly bound to the the surface of the particle

• Strong interactions

• Ions move with the particles

Outer layer (diffuse layer):

• Ions are less tightly bound and are constantly in motion

• Weaker interactions to the particle surface

Explaining DVLO Theory

Zeta potential

• Shows the difference in electrical potential between the inner layer (close to the particle) and outer layer (further away from the particle)

• Tells is how strong the repulsive forces (V_R) are that push other particles away

Very positive or very negative zeta potential:

• Large difference in charge between inner and outer layer

• Strong repulsive forces so particles more likely to stay apart and not stick together

• Good stability

Zeta potential close to 0

• Difference in charge between inner and outer layer is small

• Minimal repulsive forces so particles are more likely to be attracted to each other and clump

• Poor stability

Explaining DVLO Theory

Why does potential fall to 0 after the Debye-Huckel distance?

• As we move away from the particle surface, the number of counter-ions decreases and the number of same charge ions increases

• When we get a certain distance from the particle (the edge of the diffuse layer) there is an equal number of positive and negative ions

• So there is a potential of 0 after the Debye-huckel distance

Explaining DVLO Theory

How does this link to flocculation

• V_T = V_A + V_R

• For flocculation to happen, the attractive forces V_A must be strong enough to overcome the repulsive forces V_R

• So we must decrease V_R

• We cannot control V_A

• However we can control V_R. V_R depends on:

  1. The surface charge

  2. The thickness of the double layer (distance over which potential falls to 0)

In a potential x distance graph plotting V_R, V_T and V_A, label the primary maximum, secondary minimum and primary minimum

What happens at the primary minimum?

Caking » the particles a small distance away from each other

What happens at the secondary minimum?

Flocculation » this is the ideal distance we want the particles to be away from each other

What determines the stability of the colloidal system?

• When particles are close together, attractive forces dominate

• This gives an energy minimum

• Which causes clumping

• When particles are slightly further away from each other , they experience repulsive forces due to their electric double layers

• This creates an energy maximum

• Which acts as a barrier to prevent particles from coming too close, so particles remain dispersed

If the energy maximum is:

Large » particles stay dispersed

Small » particles will aggregate

Methods to prevent caking

1. Add an electrolyte

2. Add a surfactant

3. Add a polymer

What happens to a suspension when you add an electrolyte ie. Counter anions?

• Increases the Debye-huckel parameter (K) » as increases the number of charged particles in the solution

• Decreases the thickness of the electric double layer (1/K) » as it is inversely proportional to K

• Decreases zeta potential » counterions neutralise the surface of the particle = less repulsion = smaller difference in potential

• Increases the depth of the secondary minimum » repulsive forces reduced = particles more able to come close to each other = deeper secondary minimum

• Deeper secondary minimum = stronger flocculation

Compare the sedimentation in a suspension when:

1. No electrolyte is addded

2. Electrolyte is added

3. Too much electrolyte is added

1. No electrolyte

• High zeta potential

• Strong repulsion between particles

• Slow sedimentation = low sediment ratio

• Prevents liquid being trapped in the sediment

• Densely packed

• Caking

2. Electrolyte

• Zeta potential decreases

• Repulsive forces between particles decreases

• Rapid sedimeintation = high sediment ratio

• Liquid trapped in sediment

• Flocculation

3. Too much electrolyte

• Completely neutralises the surface charge on the particles

• Zeta potential decreases too much and becomes negative

• Repulsion between particles is too weak

• Leads to irreversible aggregation of particles

• Caking

As you add more electrolyte what happens to zeta potential

MORE ELECTROLYTE = ZETA POTENTIAL DECREASES

What zeta potential is ideal and does flocculation occur at?

WHEN ZETA POTENTIAL CLOSE TO 0

What is the difference between adding an electrolyte to a suspension and adding a viscosity enhancing agent?

• Electrolytes prevent caking

• Viscosity enhancing agents only delay caking

EQ:

What happens when you add KH2PO4 to a bismuth subnitrate suspension (positively charged surface)?

• Initially the suspension is deflocculated

• Adding KH2PO4 (K+, H+, PO4^3-) causes a reduction in zeta potential because the phosphate ions adsorb to the particles

• As more KH2PO4 is added, the zeta potential reduces to zero, then turns negative

• To obtain a flocculated suspension, need to control the zeta potential by adding the right amount of electrolyte

How does adding a surfactant prevent caking?

• Neutralises the surface charge of a particle

• So reduces repulsion between the particles

How does adding a polymer prevent caking?

Examples of polymers we can use

• Groups in the polymer interact with the surface of the particles

• The free end of the polymer attaches to another particle

• This causes interparticle bridging leading to flocculation

• If there are no other particles to interact with, the free end of the polymer coats the particle. This leads to a deflocculated system

• So we have to carefully control the polymer concentration

E.g. starch, alginate

Maalox Suspension

Drug class

Active ingredients

How and where do they act following oral administration?

List the excipients and identify their roles in the formulation

• Antacid (neutralises stomach acid)

• Aluminium hydroxide and Magnesium hydroxide

• Acts in the stomach to neutralise HCl, which raises pH levels

Excipients:

Citric acid » adjusts pH, enhances taste

Peppermint oil » improves taste

Mannitol » sweetener

Domiphen bromide » preservative as lots of sweeteners

Purified water » solvent

What excipient do you need in a suspension that contains water + sweeteners?

Preservatives e.g. domiphen bromide » prevents bacteria growth

What excipients should you always expect in a suspension?

• Water

• Sweetening agent

• Preservative

• Thickening agent

Nitrazepam Oral Suspension

Active ingredient

What is it used for?

Where does it act following oral administration?

Which excipient is used to increase viscosity to prevent caking?

• Nitrazepam

• Used as a sedative to treat anxiety and sleeping disorders

• Acts in the brain

• Carbocymethyl cellulose (CMC) sodium (thickening agent)

Compare Nitrazepam Oral Suspension and Maalox Suspnesion, in terms of site of action following oral administration

Nitrazepam: Acts systematically on the brain so is absorbed

Maalox: Acts locally in the stomach so does not need to be absorbed

Give 2 formulation measures you could take to reduce the sedimentation rate of solid drug particles in a suspension

1. Increase viscosity of continuous phase » by adding thickening agents such as carboxymethyl cellulose

2. Decrease particle size

Stabilising Bismuth Subnitrate by adding Phosphate Ions

What is the flocculating agent

Potassium Phosphate

Stabilising Bismuth Subnitrate by adding Phosphate Ions

How does the addition of phosphate ions prevent caking?

• Bismuth subnitrate particles are positively charged

• The negative phosphate ions adsorb onto the bismuth subnitrate particles

• This reduces the positive charge on the particles

• Increasing the phosphate ion concentrations further reduces the positive charge as more anions adsorb onto the particles

• Eventually the net charge of the bismuth subnitrate particles becomes zero

• Further addition of phosphate ions causes the charge to become negative

• This reduces repulsion between particles

• Particles aggregate more easily

• Increases particle size

• Increases settling rate

• Decreases caking

Stabilising Bismuth Subnitrate by adding Phosphate Ions

Illustrate with a sketched graph how you expect the sediment volume to change as increasing amounts of phosphate ions are added to bismuth subnitrate suspension

Stabilising Bismuth Subnitrate by adding Phosphate Ions

Method

1. Prepare suspending mediums from stock electrolyte solution of 320mM KH2PO4 solution

2. Weigh 10g of bismuth subnitrate in a weighing boats and transfer to 100mL measuring cylinders

3. Add suspending medium to each, stopper cylinder and shake to disperse bismuth subnitrate particles in liquid medium

4. Invert cylinder to ensure no solid particles are stuck to the base

5. Leave suspensions to stand and measure sediment volume the next day

6. Plot a graph of electrolyte concentration against sediment ratio R

   R = volume of sediment / total suspension volume

Preparation of Calamine Lotion

What is the pharmaceutical function of each of these ingredients in the formulation the calamine lotion suspension:

1. Zinc oxide

2. Glycerin

3. Bentonite

4. Sodium Citrate

1. Stabilises pH, enhances stability

2. Increases viscosity

3. Increases viscosity

4. Maintains pH, prevents aggregation of particles

A pharmaceutical company sells a medicine comprising ibuprofen particles in an aqueous medium, which they describe as a colloidal dispersion. Given that the particle size is measured to be 2.5um, comment on this description

• Not colloidal

• Particles too big

• Colloid particles must be <1mL

Distinguish clearly between the terms coagulation and flocculation

Coagulation: particles are bound together by strong forces, very close together and often cannot be redispersed » leads to caking

Flocculation: particles are bound together weakly, not as close together, can be redispersed

A pharmaceutical company is attempting to prepare a suspension of a drug D (structure shown).

1. On their first attempts, the company find that the suspension is poor quality, with significant amounts of clumping and clinging observed. Explain these observations and suggest a possible solution to these problems.

2. Eventually the company is able to implement a solution to the clumping and clinging problems. However now they find that the suspension tends to cake upon standing. Explain what is meant by the term caking, why it arises and why it is problematic.

3. The company decide to add K3PO4 to their suspension. Explain why they made this decision, and what affect the K3PO4 will have.

1. Clumping

   • Particles stick together closely so minimum surface area exposed to continuous phase

   • Usually floats to the top

   Clinging

   • Particles cling to the sides of the container

   Solution

   • Add a wetting agent

• Caking is the formation of a dense, compact sediment in a suspension that is difficult to redisperse

• It occurs when particles in the suspension aggregate and settle at the bottom, forming a hard mass due to strong forces between the particles

  » due to inadequate particle stabilization, insufficient repulsive forces, changes in the suspension’s viscosity

• Problematic as leads to inaccurate dosing

• K3PO4 is an electrolyte

• The negative phosphate ions bind to the surface of the positive particles

• This decreases the zeta potential

• This produces flocs

• Easy to disperse

• So no caking

Give the mathematical expression for the sediment ratio

R = height of sedimented layer (h) / initial height of suspension (h₀)

A plot of sediment ratio vs time for a suspension of drug in water is plotted below. Sketch on this plot the curve you would expect if:

(i) A viscosity enhancing agent is added to the suspension

(ii) A flocculating agent is added to the suspension

Explain the differences between the sediment ratio vs time plot for the suspension comprising the drug and water alone and that where a flocculating agent is added

Suspension with Drug and Water Alone (No Flocculating Agent):

• Sediment ratio decreases gradually over time as particles settle slowly.

• Particles form a dense, compact sediment (caking), making redispersion difficult.

• The final sediment volume is small due to tight packing of particles.

Suspension with a Flocculating Agent:

• Sediment ratio decreases more rapidly at first because flocculated particles settle faster.

• Particles form a loose, porous sediment that is easy to redisperse.

• The final sediment volume is higher since flocs trap more liquid, preventing compact packing.

Describe with diagrams how the addition of a polymer to a suspension can help prevent caking. Why is it important to ensure that the correct amount of polymer is added?

• Groups in the polymer interact with the surface of the particles

• The free end of the polymer attaches to another particle

• This causes interparticle bridging leading to flocculation

• If there are no other particles to interact with, the free end of the polymer coats the particle. This leads to a deflocculated system

• So we have to carefully control the polymer concentration