Suspensions

Question 1

Liquid and semi-solid dosage forms:

Answer 1

• Solutions
• Suspensions
• Ointments
• Creams

Question 2

Why do we need them?

! Stability

Answer 2

• Chemical and physical stability (i.e. dose uniformity)
• Although the particles are solid (and are therefore chemically more stable) the overall product (due to particle size, for example) behaves like a liquid, ensuring good compliance

Question 3

Why do we need them?

! Compliance

Answer 3

• Easy to swallow (children, elderly)
• Easy to divide the dose and to control the dose
• Can mask unpleasant tastes (i.e. chlorampenicol, where the ester form has a more acceptable taste, and is given as a suspension)
• Fast pharmaceutical “action” (i.e. fast onset, absorption, etc.)

Question 4

Some examples

Answer 4

A wide range of dosage forms:

• Oral suspensions: Aluminium hydroxide or magnesium hydroxide antacid suspensions
• Parenteral suspensions: Insulin zinc suspension BP
• Topical applications: Calamine lotion BP
• Dry powder for suspensions: Barium sulphate for suspension BP

Question 5

Desirable properties of suspensions

Answer 5

• The dispersed particles should settle slowly: This allows an accurate and uniform dose to be taken from the medicine
• The particles should remain flocculated (evenly distributed throughout the liquid media) and should be readily dispersed upon shaking
• Caking – aggregation of particles – should be avoided, for reasons of both uniformity of drug distribution and physical stability / re- suspension of the product
• Ease of use
  ! Viscosity: the product must be easily dispersed from its container, so viscosity should be appropriate (neither too thick nor too thin)
• Particle size
  ! Should remain reasonably constant; this assists stability, re-dispersion and may minimise caking and settling of the suspended material

Question 6

Sedimentation

Answer 6

- Particles will fall under the force of gravity according to Stokes Law:
v = 2a2 g (σ- p)/9n
a – particle radius 
σ - density
ρ - vehicle density 
η- viscosity
g – gravity 
ν - velocity

• If V0 is the height of the whole pharmaceutical product, and Vu the height of the sediment:
• We define the sedimentation volume, F, as the ratio of Vu/V0

Question 7

Wetting of particles - 2 powders

Answer 7

• Hydrophobic powders: (lipid powders)
  ! … have a high contact angle (aggregate into little balls)
  ! They are not easily wetted and tend to float on the surface of the liquid
  ! Examples of hydrophobic powders include sulphur or magnesium stearate
• Hydrophilic powders:
  ! … tend to have a low contact angle
  ! As a consequence of their contact angle, they are readily wetted
  ! Examples include zinc oxide and magnesium carbonate

Question 8

Flocculation and deflocculation

Answer 8

Table - slide 24

Question 9

Degree of flocculation

Answer 9

! In a deflocculated system: The sedimentation volume is given by Fu = Vu/V0
! In a flocculated system: The sedimentation volume is given by Ff = Vf/V0
! The degree of flocculation is given by β=Ff/Fu=Vf/Vu
! A bigger value of β means better flocculation

Question 10

Viscosity modifiers

Answer 10

! Polysaccharides
! Acacia: often used with other thickeners (i.e. those above), common in extemporaneous products
! Tragacanth: also used in extemporaneous products, slow to hydrate, non-Newtonian behaviour
! Alginates; starch; Xantham Gum
! Water-soluble celluloses
! There are a wide range of variants of all the above materials authorised for pharmaceutical use
! Hydrated silicates, such as bentonite, Veegum (MgAl silicate)
! Highly absorbent ! Non-Newtonian
! Carbomers
! Synthetic polymers of acrylic acid
! There are a wide range of variants of all the above materials authorised for pharmaceutical use

Question 11

Other additives

Answer 11

! Buffering agents 
! Sweeteners
! Artificial (i.e. E954 saccharin, E951 aspartame) and “natural” materials
! Flavours
! Colouring agents 
! Preservatives

Question 12

Manufacture

! A range of methods:

Answer 12

! Extemporaneous – mortar and pestle
! High-shear mixers
! Homogenisers
! Ball mills

Question 13

“Ostwald Ripening”equation

Answer 13

The solubility of particles depends on their particle size

In S/SO = 2gammaM/ 2.303 RT pr

As size (r) decreases, solubility increases

Question 14

Evaluation of physical stability

Answer 14

! Aesthetic tests
! General appearance, colour, odour, taste
! pH
! Includes measurement of zeta potential and solubility of some drugs
! Sedimentation rate
! Particle size and form (i.e. whether or not it is crystalline)
! Re-dispersion and centrifugation tests
! Rheological measurement
! Freeze-Thaw temperature cycling
! Compatibility with container and cap liner
! Dose uniformity
! Microbial testing

Question 15

Evaluation of chemical stability

Answer 15

! Chemical degradation is normally in the solution phase of a suspension
! The kinetic processes may be different than a true solution
! May result in a change of pH, and therefore physical stability

Question 16

What is a suspension?

Answer 16

A coarse disperse system where an insoluble solid is dispersed in a liquid medium

• Disperse phase
  ! Solid particles, usually > 0.1μm
• Disperse medium
  ! For most pharmaceutical applications, this is usually an
  aqueous media
  ! However, it may infrequently be an organic or oily material

Question 17

Why do we need them?

Answer 17

! Drug is insoluble
! Drug is more stable in a suspension (or an emulsion) than in another dosage form
! There may be a need to control the rate of release of the drug
! Drug has bad taste (if taken orally) - compliance

Question 18

Further examples

Answer 18

! Insoluble or poorly soluble drugs (i.e. prednisolone suspension)
! To prevent degradation of drug or to improve stability of the drug (i.e. oxytetracycline suspension)
! Masking of bitter tastes (i.e. chloramphenicol palmitate
suspension)
! Topical application (i.e. calamine lotion).
! Parenteral preparation – in order to control the rate of drug
absorption (penicillin, procaine)
! Vaccines for immunisation (Cholera vaccine)
! X-ray contrast agents (Barium sulphate)

Question 19

Control of particle size

Answer 19

! Texture
! Larger particles, generally those over 5μm in diameter,
will result in a gritty texture
! Dose uniformity
! Variable dissolution and bioavailability
! Sedimentation
! Physical stability and uniformity of dose

Question 20

Wetting of particles

Answer 20

• Powders may often float on top of a liquid. This is often due to:
  ! The presence of an absorbed layer of air
  ! The lipophilic nature of certain materials or contaminants
  ! Poor properties of “wettability” – this generally refers to the contact angle of the particle and the surface.

Question 21

Improvement of particle wetting

Answer 21

! Use “wetting” agents…
! This improves “wettability” of hydrophobic powders by reducing surface tension between the particle and the liquid surface, and reducing the contact angle.
! Only wettable (and “wetted”) particles can be readily dispersed into the liquid and remain adequately dispersed.

Question 22

Improvement of particle wetting

! Materials used to improve particle wetting:

Answer 22

! Choice of material depends on the route of administration

Question 23

Improvement of particle wetting: surfactants

Answer 23

! Oral route:
! Surfactants, such as polysorbates sorbitan esters, are
commonly used (Tweens and Spans, respectively) ! i.v.
! Lecithin, polysorbates and poloxamers and related materials
! Used in relatively low (ca. 0.1% w/w) concentrations, compared to other uses
! A disadvantage is that they may cause excessive foaming in the product

Question 24

Improvement of particle wetting: hydrophilic colloids

Answer 24

! Examples include:
! Acacia, bentonite, tragacanth, alginates, xantham gum
and carious celluose derivatives
! The particles that are intended for suspension generally become more “wettable” after being coated with a layer of hydrophilic colloid
! Hydrophilic colloids also act as suspending agents, usually as a result of their viscosity

Question 25

Improvement of particle wetting: solvents

Answer 25

Examples include: ! Various alcohols (usually ethanol), glycerol and glycols ! Different solvents may exert a range of effects, including the ability to penetrate into loose aggregations of particles, and in doing so displacing the air adsorbed within such structures

Question 26

Flocculation | ! IUPACdefinition:

Answer 26

! “a process of contact and adhesion whereby the particles of a dispersion form larger-size clusters.” ! Flocculation describes the removal of a sediment from a fluid. ! In addition to occurring naturally, flocculation can also be forced through agitation or the addition of flocculating agents.

Question 27

Flocculation and viscosity

Answer 27

! Viscosity can be increased to reduce the rate of suspension (i.e. Stokes-Einstein equation) ! However, sedimentation will almost always happen to some extent. Increasing the viscosity helps in the short term but, upon storage, a high viscosity can make a product difficult to redisperse. ! So, a compromise between viscosity, degree of flocculation and ease of resuspension is the normal solution

Question 28

Electrolytes

Answer 28

! The control of zeta-potential and interaction energy. ! Zeta potential describes the electrical potential in the interfacial double layer at the boundary of different regions of, in this case, a suspension (between the solid and liquid particles). ! It is the potential difference between the dispersion medium and the stationary layer of fluid attached to the dispersed particle in the suspension. ! The concentration of electrolytes is important in maintaining the stability of the suspension. ! If the concentration of the electrolytes is too high, it may result in charge repulsion and caking of the suspended agent. ! This is reduced or minimised by buffering the formulation to control pH and ionisation, and electrolyte concentration.

Question 29

Polymers

Answer 29

! Cross-linking ! “Bridge flocculation” ! Starch, alginates, tragacanth, cellulose derivatives ! Selecting the correct concentration will be important for determining viscosity of, for example, the liquid phase

Question 30

“Ostwald Ripening” | ! IUPAC definition:

Answer 30

! The change of an in homogeneous structure over time. Over time, small crystals (or sol particles) dissolve, and redeposit onto larger crystals or sol particles ! Suspensions contain particles suspended in saturated or supersaturated solutions of the drug substance ! In thermodynamic terms: ! In such a system, small particles will tend to dissolve, and large particles will tend to get larger ! The system will change and may become unsuitable for use.

Question 31

Polymorphism

Answer 31

! Despite being chemically “the same”, some substances can exist in more than one crystalline form. ! Different polymorphic forms (polymorphs) have different properties – in pharmaceutical terms this can include different physical stability ! Solubility can also differ between polymorphs of the same material

Question 32

Polymorphism | ! Examples

Answer 32

! Examples include spironolactone, paracetamol and cortisone ! E.g. cortisone acetate suspension: ! It has at least five common crystal forms ! Four unstable forms can change to the stable form in the presence of water ! Caking is often observed when the crystal form changes ! Therefore, to prepare the material for pharmaceutical use, it must be in the correct crystal form only; factors that will affect a material’s properties include temperature, the presence of water and the application of shear stress (i.e. by grinding) in water

Question 33

Inhibition of crystal growth

Answer 33

! Polymers ! Various polymers will form a protective layer around the particles ! Surfactants ! Most will reduce crystallisation but a few might increase it ! Temperature ! Temperature influences solubility and this can change the degree of saturation or supersaturation in solution

Question 34

Example formulation | ! Calamine lotion BP

Answer 34

- Calamine 30g - Zinc oxide 10g - Bentonite 6g (thickening agent) - Sodium citrate 1g (controls flocculation) - Liquefied phenol 0.5mL (preservative) - Glycerol 5mL (thickening agent; also helps the product adhere better to the skin) - Water to 200mL