Suspensions Flashcards
Liquid and semi-solid dosage forms:
- Solutions
- Suspensions
- Ointments
- Creams
Why do we need them?
! Stability
- 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
Why do we need them?
! Compliance
- 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.)
Some examples
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
Desirable properties of suspensions
- 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
Sedimentation
- 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
Wetting of particles - 2 powders
- 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
Flocculation and deflocculation
Table - slide 24
Degree of flocculation
! 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
Viscosity modifiers
! 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
Other additives
! Buffering agents ! Sweeteners ! Artificial (i.e. E954 saccharin, E951 aspartame) and “natural” materials ! Flavours ! Colouring agents ! Preservatives
Manufacture
! A range of methods:
! Extemporaneous – mortar and pestle
! High-shear mixers
! Homogenisers
! Ball mills
“Ostwald Ripening”equation
The solubility of particles depends on their particle size
In S/SO = 2gammaM/ 2.303 RT pr
As size (r) decreases, solubility increases
Evaluation of physical stability
! 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
Evaluation of chemical stability
! 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
What is a suspension?
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
Why do we need them?
! 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
Further examples
! 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)
Control of particle size
! 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
Wetting of particles
- 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.
Improvement of particle wetting
! 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.
Improvement of particle wetting
! Materials used to improve particle wetting:
! Choice of material depends on the route of administration
Improvement of particle wetting: surfactants
! 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
Improvement of particle wetting: hydrophilic colloids
! 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
Improvement of particle wetting: solvents
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
Flocculation
! IUPACdefinition:
! “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.
Flocculation and viscosity
! 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
Electrolytes
! 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.
Polymers
! 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
“Ostwald Ripening”
! IUPAC definition:
! 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.
Polymorphism
! 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
Polymorphism
! Examples
! 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
Inhibition of crystal growth
! 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
Example formulation
! Calamine lotion BP
- 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
