Suspensions 5/19/2015BA-FP-JU-C

suspensions A suspension: is a disperse system in which one substance (the disperse phase) is distributed in particulate form throughout another (the continuous phase) (i.e. at least 2 phases). According to the particle size of the dispersed phase, suspensions are divided into: Coarse suspension: which is a dispersion of particles with a mean diameter greater than 1 µm. Colloidal suspension is a dispersion of particles with a mean diameter less than 1 µm. 5/19/2015BA-FP-JU-C

Pharmaceutical application of suspensions Why suspensions? Against solid dosage forms: If patient has a difficulty of swallowing solid dosage forms (a need for oral liquid dosage form). Faster rate of dissolution and oral absorption than solid dosage forms, yet slower than solutions. Bulky insoluble powders as kaolin or chalk are better formulated as suspensions so that they are easier to take. 5/19/2015BA-FP-JU-C

Pharmaceutical application of suspensions Why suspensions? Against solutions: Drugs that have very low solubility are usefully formulated as suspensions. Drugs that have an unpleasant taste in their soluble forms (e.g., chloramphenicol (soluble) vs. chloramphenicol palmitate (insoluble )). Prolongation of effect (e.g. I.M and S.C. suspensions). Stability and instability issues: Insoluble forms of drugs may prolong the action of a drug by preventing rapid degradation of the drug in the presence of water (e.g., Oxytetracycline hydrochloride (soluble, hydrolyses rapidly) vs oxytetracycline calcium salt (insoluble, stable). Non-aqueous suspensions (tetracycline hydrochloride in coconut oil) Reconstitution (ampicillin suspension). 5/19/2015BA-FP-JU-C

Properties of a good pharmaceutical suspension There is ready redispersion of any sediment which accumulates on storage. After gentle shaking, the medicament stays in suspension long enough for a dose to be accurately measured. The suspension is pourable. Particles in suspension are small and relatively uniform in size. so that the product is free from a gritty texture. 5/19/2015BA-FP-JU-C

Formulation of suspensions Formulation problems 1. Sedimentation. 2. Thermodynamic instability. 3. Wetting. 5/19/2015BA-FP-JU-C

Sedimentation The factors affecting the rate of sedimentation are in Stokes' equation: Where v= velocity of sedimentation of a spherical particle of radius r, and density σ, in a liquid of density ρ, and viscosity ŋ, and where g is the acceleration due to gravity. 5/19/2015BA-FP-JU-C

Thermodynamic instability Interfacial free energy (IFE). IFE = Interfacial tension * surface area Flocculation Aggregation 5/19/2015BA-FP-JU-C

Flocculation The natural tendency of particles towards aggregation will determine the properties of a suspension. Whether or not a suspension is flocculated or deflocculated depends on the relative magnitude of repulsive/attractive forces between particles. 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. 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. 5/19/2015 BA-FP-JU-C

The insoluble medicament may be : 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. Indiffusible solids: Most insoluble solids are not easily wetted, and some particles may form large porous clumps in the liquid, whereas others may remain on the surface. 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 includes aspirin, phenobarbital, sulfadirnidine and chalk, and for external use calamine, hydrocortisone, su1phur and zinc oxide. 5/19/2015BA-FP-JU-C Wetting

Because of the high interfacial tension between indiffusible solids and water; air may be trapped in these poorly wetted particles 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 inter- particular forces thereby affecting flocculation. 5/19/2015BA-FP-JU-C

Wetting Wetting agents: 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 such as polysorbates (tweens) and sorbitan esters (spans) are used for internal preparations. Sodium lauryl sulphate and quillaia tincture are used in external preparations. Solvents such as ethanol, glycerol and the glycols also facilitate wetting. 5/19/2015BA-FP-JU-C

Suspending agents Suspending agents increase the viscosity of the vehicle, thereby slowing down sedimentation. Most agents can form thixotropic gels which are semisolid on standing, but flow readily after shaking. Care must be taken when selecting a suspending agent for oral preparations. Suspending agents can be divided into five broad categories: natural polysaccharides, semi-synthetic polysaccharides, clays, synthetic thickeners and miscellaneous compounds. 5/19/2015BA-FP-JU-C

Suspending agents Natural polysaccharides The main problem with these agents is their natural variability between batches and microbial contamination. These materials should not be used externally as they leave a sticky feel on the skin. They include tragacanth, acacia gum, starch, agar, guar gum, carrageenan and sodium alginate. Tragacanth: Is a widely used suspending agent and is less viscous at pH As a rule: 0.2g tragacanth powder is added per 100 mL suspension or 2g compound tragacanth powder per 100 mL suspension. Compound Tragacanth Powder BP 1980 contains tragacanth, acacia, starch and sucrose and so is easier to use. Tragacanth powder requires to be dispersed with the insoluble powders before water is added to prevent clumping. 5/19/2015BA-FP-JU-C

Suspending agents Semi-synthetic polysaccharides These are derived from the naturally occurring polysaccharide cellulose. Examples include Methylcellulose (Cologel ®, Celacol®) Hydroxyethylcellulose (Natrosol 250®) Sodium carboxymethylcellulose (Carmellose sodium®) Microcrystalline cellulose (Avicel®). 5/19/2015BA-FP-JU-C

Suspending agents Clays These are naturally occurring inorganic materials which are mainly hydrated silicates. Examples include bentonite and magnesium aluminium silicate (Veegum®). 5/19/2015BA-FP-JU-C

Suspending agents Synthetic thickeners: These were introduced to overcome the variable quality of natural products. Examples include: Carbomer (Carboxyvinyl polymer, Carbopol®), Colloidal silicon dioxide (Aerosil®, Cab-o-sil®) Polyvinyl alcohol (PVA). Miscellaneous thickeners: Gelatin used as a suspending agent and a viscosity increasing agent 5/19/2015BA-FP-JU-C

Preservation of a suspension Water is the most common source of microbial contamination. 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. 5/19/2015BA-FP-JU-C

Formulation of suspension 1. Control particle size. On a small scale. this can be done using a mortar and pestle. to grind down ingredients to a fine powder. 2. Use a thickening agent to increase viscosity of vehicle by using suspending or viscosity-increasing agents. 3. Use a wetting agent. 5/19/2015BA-FP-JU-C

The dispensing of suspensions Method of preparation A. Crystalline and granular solids are finely powdered in the mortar. The suspending agent should then be added and mixed thoroughly in the mortar. Avoid gumming or caking. B. Gradual addition of vehicle, make a paste then continue till become smooth and pourable, rinse and up to volume in a tared bottle. 5/19/2015BA-FP-JU-C

Variations: If wetting agents are included in the formulation, add them before forming the paste. If syrup and/or glycerol are in the formulation, use this rather than water to form the initial paste. If soluble solids are being used, dissolve them in the vehicle before or after making the paste. Leave addition of volatile components, colourings or concentrated flavouring tinctures such as chloroform spirit, liquid liquorice extract and compound tartrazine solution until near the end. 5/19/2015BA-FP-JU-C The dispensing of suspensions

Preparation of suspension from oral solid dosage form 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 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. 5/19/2015BA-FP-JU-C

Preparation of suspension from dry powders and granules for reconstitution Reconstitution because of chemical or physical instability. Loosening of powder from bottom of the container. The specified amount of cold, purified water should then be added, sometimes in two or more portions with shaking. some preparations may be prepared immediately before taking from individually packed sachets of powder or from bulk solids. 5/19/2015BA-FP-JU-C

Containers for suspension 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. 5/19/2015BA-FP-JU-C

Special label and advice for suspension The most important additional label for suspensions is ' Shake well before use ', 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 from reconstituting dry powders, may need to be stored in a refrigerator. Extemporaneously prepared and reconstituted are required to be recently or freshly prepared, with a 1-4- week expiry date. 5/19/2015BA-FP-JU-C

150ml Kaolin and Morphine Mixture BP. Master formula150ml Light kaolin2g30g Sodium bicarbonate500mg7.5g Chloroform and morphine tincture0.4ml6ml Waterto 10ml to 150ml 5/19/2015BA-FP-JU-C

Chalk Mixture, Paediatric BP. Mitte 100ml Master formula100ml Chalk100mg2g Tragacanth10mg200mg Syrup0.5ml10ml Concentrated cinnamon water0.02ml0.4ml Double strength chloroform water2.5ml50ml Waterto 5ml to 100ml 5/19/2015BA-FP-JU-C

Spironolactone suspension 15mg/5ml. Sig.5ml t.d.s. Mitte 100ml. For a 4-year-old child. Master formula100ml Spironolactoneq.s.*300mg Compound orange spirit0.2%0.2ml Cologel 20%20ml Waterto 100%100ml *q.s. means sufficient 5/19/2015BA-FP-JU-C

Menthol and Eucalyptus Inhalation BP Mitte 100ml Master formula Menthol2g Eucalyptus oil10ml Light magnesium carbonate7g Waterto 100ml 5/19/2015BA-FP-JU-C

200ml Calamine Lotion BP Master formula200ml Calamine15g30g Zinc oxide5g10g Bentonite3g6g Sodium citrate500mg1g Liquified phenol0.5ml1ml Glycerol5ml10ml Waterto 100ml to 200ml 5/19/2015BA-FP-JU-C

Key points Suspensions can be used to administer an insoluble solid by the oral route. Suspensions may be used to replace tablets, to improve dissolution rate, to prolong action and to mask a bad taste. Solids may be diffusible or indiffusible and require different dispensing techniques. Stokes' equation can be applied when formulating a suspension to help ensure accurate dosage of the drug. Flocculated particles settle quickly and redisperse easily, whilst deflocculated particles settle slowly but tend to cake. 5/19/2015BA-FP-JU-C

Key points Hydrophobic solids may require wetting agents. Suspending agents are added to slow down the rate of settling of the solid. Suspending agents may be natural polysaccharides, semi synthetic polysaccharides, clays or synthetic polymers. Some suspensions are made by adding water to reconstitute manufactured powders when stability is a problem. Shake well before use' and 'Store in a cool place‘ should be part of the labels on a suspension. Inhalations are suspensions of a volatile material adsorbed onto a diffusible solid. 5/19/2015BA-FP-JU-C