Chapter 31 Suspensions
Introduction
Suspensions contain one or more insoluble medicaments in a vehicle, with other additives such as preservatives, flavours, colours, buffers and stabilizers. Most pharmaceutical suspensions are aqueous, but an oily vehicle is sometimes used. Suspensions may be used for oral administration, inhalation, topical application, as ophthalmic preparations, for parenteral administration and as aerosols.
A pharmaceutical suspension may be defined as a disperse system in which one substance (the disperse phase) is distributed in particulate form throughout another (the continuous phase). Most are classified as a coarse suspension which is a dispersion of particles with a mean diameter greater than 1 μm. A colloidal suspension is a dispersion of particles with a mean diameter less than 1 μm. Suspended solids slowly separate on standing, but redispersion may be difficult if they form a compacted sediment.
Pharmaceutical applications of suspensions
Suspensions may be used pharmaceutically for a number of reasons. Some are given below:
Properties of a good pharmaceutical suspension
In preparing a pharmaceutically elegant product, several desirable properties are sought:
Formulation of suspensions
The three steps that can be taken to ensure formulation of an elegant pharmaceutical suspension are:
Some of the theoretical and practical aspects of these will be considered in the context of extemporaneous dispensing. Further details about the industrial aspects are given in Aulton (2007).
The insoluble medicament may be a diffusible solid or an indiffusible solid:
Diffusible solids (dispersible solids). These are insoluble solids that are light and easily wetted by water. They mix readily with water, and stay dispersed long enough for an adequate dose to be measured. After settling they redisperse easily. Examples include magnesium trisilicate, light magnesium carbonate, bismuth carbonate and light kaolin (see Example 31.1).
Indiffusible solids. Most insoluble solids are not easily wetted, and may form large porous clumps in the liquid. These solids will not remain evenly distributed in the vehicle long enough for an adequate dose to be measured. They may not redisperse easily. Examples for internal use include aspirin, phenobarbital, sulfadimidine and chalk (see Example 31.2) and for external use calamine, hydrocortisone, sulphur and zinc oxide.
Problems encountered when formulating insoluble solids into a suspension
Various factors need to be considered when formulating insoluble solids into a suspension.
Sedimentation
The factors affecting the rate of sedimentation of a particle are described in Stokes’ equation:
where y = velocity of a spherical particle of radius r, and density ρ1, in a liquid of density ρ2, and viscosity η, and where g is the acceleration due to gravity.
The basic consequences of this equation are that the rate of fall of a suspended particle in a vehicle of a given density is greater for larger particles than it is for smaller particles. Also, the greater the difference in density between the particles and vehicle, the greater will be the rate of descent. Increasing the viscosity of the dispersion medium, within limits so that the suspension is still pourable, will reduce the rate of sedimentation of a solid drug. Thus a decrease in settling rate in a suspension may be achieved by reducing the size of the particles and by increasing the density and the viscosity of the continuous phase.
Flocculation
The natural tendency of particles towards aggregation will determine the properties of a suspension. In a deflocculated suspension, the dispersed solid particles remain separate and settle slowly. However, the sediment that eventually forms is hard to redisperse and is described as a ‘cake’ or ‘clay’. In a flocculated suspension, individual particles aggregate into clumps or floccules in suspension. Because these flocs are larger than individual particles, sedimentation is more rapid, but the sediment is loose and easily redispersible. Excess flocculation may prevent ‘pourability’ due to its effect on rheological properties.
The ideal is to use either a deflocculated system with a sufficiently high viscosity to prevent sedimentation, or controlled flocculation with a suitable combination of rate of sedimentation, type of sediment and pourability.
Wetting
Air may be trapped in the particles of poorly wetted solids which causes them to float to the surface of the preparation and prevents them from being readily dispersed throughout the vehicle. Wetting of the particles can be encouraged by reducing the interfacial tension between the solid and the vehicle, so that adsorbed air is displaced from solid surfaces by liquid. Suitable wetting agents have this effect, but decrease interparticular forces thereby affecting flocculation.
Hydrophilic colloids such as acacia and tragacanth can act as wetting agents. However, care should be taken when using these agents as they can promote deflocculation. Intermediate HLB (hydrophilic–lipophilic balance) surfactants (see Ch. 32) such as polysorbates and sorbitan esters are used for internal preparations. Solvents such as ethanol, glycerol and the glycols also facilitate wetting. Sodium lauryl sulphate and quillaia tincture are used in external preparations.
Suspending agents
Suspending agents increase the viscosity of the vehicle, thereby slowing down sedimentation. Most agents can form thixotropic gels which are semi-solid on standing, but flow readily after shaking. Care must be taken when selecting a suspending agent for oral preparations, as the acid environment of the stomach may alter the physical characteristics of the suspension, and therefore the rate of release of the drug from suspension. Some suspending agents may also bind to certain medicaments, making them less bioavailable.
Suspending agents can be divided into five broad categories: natural polysaccharides, semi-synthetic polysaccharides, clays, synthetic thickeners and miscellaneous compounds. Brief information on these classes of suspending agents is given below, with more detailed information available from the Pharmaceutical Codex or Aulton (2007).
Natural polysaccharides
The main problem with these agents is their natural variability between batches and microbial contamination. Tragacanth is a widely used suspending agent and is less viscous at pH 4–7.5. As a rule of thumb, 0.2 g Tragacanth Powder is added per 100 mL suspension or 2 g Compound Tragacanth Powder per 100 mL suspension. Tragacanth Powder requires to be dispersed with the insoluble powders before water is added to prevent clumping (see Example 31.2). Compound Tragacanth Powder BP 1980 contains tragacanth, acacia, starch and sucrose and so is easier to use. Other examples include acacia gum, starch, agar, guar gum, carrageenan and sodium alginate. These materials should not be used externally as they leave a sticky feel on the skin.
Semi-synthetic polysaccharides
These are derived from the naturally occurring polysaccharide cellulose. Examples include methylcellulose (Cologel®, Celacol®), hydroxyethylcellulose (Natrosol 250®), sodium carboxymethylcellulose (Carmellose sodium) and microcrystalline cellulose (Avicel®).
Clays
These are naturally occurring inorganic materials which are mainly hydrated silicates. Examples include bentonite and magnesium aluminium silicate (Veegum®).
Preservation of suspensions
Water is the most common source of microbial contamination. All pharmaceutical preparations that contain water are therefore susceptible to microbial growth. Also the naturally occurring additives such as acacia and tragacanth may be sources of microbes and spores. Preservative action may be diminished because of adsorption of the preservative onto solid particles of drug, or interaction with suspending agents. Useful preservatives in extemporaneous preparations include chloroform water, benzoic acid and hydroxybenzoates.
The dispensing of suspensions
The method of dispensing suspensions is the same for most, with some differences for specific ingredients.
Variations
Most ‘official’ suspensions will be prepared from the constituent ingredients. There may be some occasions where an oral solid dosage form, such as a tablet or capsule, will have to be reformulated by the pharmacist into an oral suspension, e.g. where the medicine is for a child (see Example 31.3). It is important to obtain as much information (physical, chemical and microbiological) as possible about the manufactured drug and its excipients. This can usually be obtained from the manufacturer. Typically, the tablet will be crushed or capsule contents emptied into the mortar and a suspending agent added. A paste is formed with the vehicle and then diluted to a suitable volume, with the addition of any other desired ingredients such as preservative or flavour. A short expiry of no more than 2 weeks (more likely to be 7 days) should be given owing to the lack of knowledge about the stability of the formulation.
Preparation of suspensions from dry powders and granules for reconstitution
Suspensions may have to be prepared from previously manufactured dry powders or granules if the liquid preparation has a limited shelf life because of chemical or physical instability. Powders should firstly be loosened from the bottom of the container by lightly tapping against a hard surface. The specified amount of cold, purified water should then be added, sometimes in two or more portions, with shaking, until all the dry powder is suspended. The container is usually over-sized in order to allow adequate shaking for reconstitution. The patient may prepare some suspensions immediately before taking from individually packed sachets of powder or from bulk solids. This is considered in more detail in Chapter 35.
Containers for suspensions
Suspensions should be packed in amber bottles, plain for internal use and ribbed for external use. There should be adequate air space above the liquid to allow shaking and ease of pouring. A 5 mL medicine spoon or oral syringe should be given when the suspension is for oral use.
Special labels and advice for suspensions
The most important additional label for suspensions is ‘Shake well before use’, as some sedimentation of medicament would normally be expected. Shaking the bottle will redisperse the medicament and ensure that the patient can measure an accurate dose.
‘Store in a cool place’. Stability of suspensions may be adversely affected by both extremes and variations of temperature. Some suspensions, such as those made by reconstituting dry powders, may need to be stored in a refrigerator.
Extemporaneously prepared and reconstituted suspensions will have a relatively short shelf life. They are usually required to be recently or freshly prepared, with a 1–4-week expiry date. Some official formulae state an expiry date, but many do not. The pharmacist may have to make judgments about the expiry date for a particular preparation, based on its constituents and likely storage conditions. The manufacturer’s literature for reconstituted products will give recommended storage conditions.
Inhalations
Suspensions are useful formulations for inhalations. The volatile components are adsorbed onto the surface of a diffusible solid to ensure uniform dispersion throughout the liquid. When hot water is added, the oils vaporize. Where quantities are not stated, 1 g of light magnesium carbonate is used for each 2 mL of oil (such as eucalyptus oil) or 2 g of volatile solid (such as menthol). An example of an inhalation is menthol and eucalyptus inhalation (see Example 31.4).
Example 31.1
150 mL Kaolin and Morphine Mixture BP.
| Master formula | For 150 mL | |
| Light kaolin | 2 g | 30 g |
| Sodium bicarbonate | 500 mg | 7.5 g |
| Chloroform and morphine tincture | 0.4 mL | 6 mL |
| Water | to 10 mL | to 150 mL |
Action and uses. As an adjunct to fluid replacement in treatment of acute diarrhoea.
Formulation notes. Light kaolin is a diffusible solid, therefore no suspending agent is required.
Method of preparation. Weigh the light kaolin and place in the mortar. Dissolve the sodium bicarbonate in about 100 mL of water. Gradually add this to the light kaolin in the mortar with mixing to disperse the solid. Add the chloroform and morphine tincture. Wash the mixture into a tared, amber medicine bottle, and make up to volume with water. Seal with a child-resistant closure. Polish and label the bottle and give a 5 mL medicine spoon with the medicine.
Shelf life and storage. Store in a cool, dry place. It is recently prepared (unless the kaolin has been sterilized), therefore a shelf life of 2–3 weeks is applicable.
Advice and labelling. ‘Shake well before use’. The usual dose is 10 mL every 4 hours in water. The importance of rehydration therapy should be stressed to the patient.
Example 31.2
Chalk Mixture, Paediatric BP. Mitte 100 mL.
| Master formula | For 100 mL | |
| Chalk | 100 mg | 2 g |
| Tragacanth | 10 mg | 200 mg |
| Syrup | 0.5 mL | 10 mL |
| Concentrated cinnamon water | 0.02 mL | 0.4 mL |
| Double strength chloroform water | 2.5 mL | 50 mL |
| Water | to 5 mL | to 100 mL |
Action and uses. As an antidiarrhoeal mixture for children, in addition to fluid replacement.
Formulation notes. Chalk is practically insoluble in water and is an indiffusible solid which requires a suspending agent. Tragacanth Powder is used in this formulation. The concentrated cinnamon water is a flavouring agent and the syrup increases the viscosity as well as acting as a sweetener. Chloroform water is the preservative.
Method of preparation. The chalk and tragacanth should be weighed and lightly mixed in a mortar and pestle. Add the syrup and mix to make a paste. The double strength chloroform water should be gradually added, with mixing, followed by the concentrated cinnamon water. The mixture should be rinsed into a previously tared 100 mL amber medicine bottle and made up to volume with water. Shake the suspension well and seal with a child-resistant closure. Polish and label the bottle and give a 5 mL medicine spoon with the medicine.
Shelf life and storage. Store in a cool, dry place. It is freshly prepared, therefore a shelf life of 1 week is applicable.
Advice and labelling. ‘Shake well before use’. A dose of 5 mL every 4 hours is normally used. Advice on the importance of fluid replacement, using oral rehydration sachets, should be given if necessary.
Example 31.3
Spironolactone suspension 15 mg/5 mL. Sig. 5 mL t.d.s. Mitte 100 mL. For a 4-year-old child.
| Master formula | For 100 mL | |
| Spironolactone | q.s.* | 300 mg |
| Compound orange spirit | 0.2% | 0.2 mL |
| Cologel | 20% | 20 mL |
| Water | to 100% | 100 mL |
*q.s. means sufficient (see Appendix 2)
Action and uses. A potassium-sparing diuretic used in oedema of heart failure and nephrotic syndrome.
Formulation notes. Spironolactone is practically insoluble in water. Cologel® (methylcellulose) acts as the suspending agent. Compound orange spirit is a flavouring agent.
Method of preparation. Tablets may be used, and sufficient crushed in a mortar and pestle to give 300 mg spironolactone (e.g. 6 × 50 mg tablets). Alternatively, weigh the powder and transfer to a mortar and pestle. Add the Cologel® and mix to a paste. Gradually add some of the water. Add the compound orange spirit. Rinse the suspension into a tared, amber medicine bottle and make up to volume with water. Shake the bottle well and seal with a child-resistant closure. Polish and label the bottle and give a 5 mL medicine spoon with the medicine.
Shelf life and storage. It is recently prepared with a shelf life of 4 weeks when stored in a refrigerator. Spironolactone should be protected from light.
Advice and labelling. ‘Shake well before use’ and ‘Give one 5 mL spoonful three times a day’. BNF Label 21 should be used. Reinforce the storage conditions.
Example 31.4
Menthol and Eucalyptus lnhalation BP 1980. Mitte 100 mL.
| Master formula | |
| Menthol | 2 g |
| Eucalyptus oil | 10 mL |
| Light magnesium carbonate | 7 g |
| Water | to 100 mL |
Action and uses. For relief of nasal congestion.
Formulation notes. Light magnesium carbonate has a large surface area and is used to adsorb the volatile ingredients which helps to ensure a uniform dispersion. Menthol is freely soluble in fixed and volatile oils, so will dissolve in the eucalyptus oil.
Method of preparation. Grind the menthol to a fine powder in a glass mortar and add the eucalyptus oil, which will dissolve the menthol. Gradually add the light magnesium carbonate to the mortar and mix well. Add the water gradually to produce a pourable suspension; this may take a while to achieve. Rinse into a tared, amber ribbed bottle and make up to volume. Seal with a child-resistant closure.
Shelf life and storage. Store in a cool, dry place. It is recently prepared, therefore a shelf life of 2–3 weeks is applicable.
Advice and labelling. ‘Shake well before use’ and ‘Not to be taken’. The patient should be told to add 1 teaspoonful to 1 pint of hot, not boiling, water. A towel should be placed over the head and bowl and the vapour inhaled for 5–10 minutes. Patients should be made aware of the potential danger of scalding to themselves and others, particularly small children.
Example 31.5
| Master formula | For 200 mL | |
| Calamine | 15 g | 30 g |
| Zinc oxide | 5 g | 10 g |
| Bentonite | 3 g | 6 g |
| Sodium citrate | 500 mg | 1 g |
| Liquefied phenol | 0.5 mL | 1 mL |
| Glycerol | 5 mL | 10 mL |
| Water | to 100 mL | to 200 mL |
Action and uses. As a cooling lotion for sunburn or skin irritation and pruritis.
Formulation notes. Calamine is a coloured zinc carbonate and is practically insoluble in water, as is zinc oxide. Both are indiffusible solids. Sodium citrate is added to control the flocculation of calamine. Bentonite is a thickening agent and glycerol will thicken the product and help powder adherence to the skin. Liquefied phenol acts as a preservative and antiseptic.
Method of preparation. The dry powders should be weighed and mixed in a mortar so that the bentonite is well distributed. Add the glycerol to the powders and mix. The sodium citrate is dissolved in about 140 mL of water, and gradually added to the mixture in the mortar, so that a smooth paste is produced. Add the liquefied phenol, taking care not to splash, as it is caustic. Transfer the mixture to a tared, amber ribbed glass bottle, adding washings from the mortar, and make up to volume. Seal with a child-resistant closure.
Shelf life and storage. Store in a cool, dry place. It is recently prepared, therefore a shelf life of 2–3 weeks is applicable.
Advice and labelling. ‘For external use only’, ‘Shake well before use’ and ‘Do not apply to broken skin’. The lotion should be applied to the affected areas when required and allowed to dry.