Suspensions PDF

SUSPENSIONS Prof Thiru Govender Discipline of Pharmaceutical Sciences Definition Dispersion of finely divided insoluble solid particles (disperse phase) in a fluid (dispersion medium). Physical Properties Of Well-Formulated Suspensions 1. Remains homogenous for at least the period between shaking the container and removing the dose. 2. Re-suspension of drug particles occurs easily with mild shaking. 3. During shelf life no hard cake is formed and is not difficult to redisperse. 4. Maintains its stability and elegance during its shelf-life. 5. Parenteral suspensions - 2 additional characteristics: o Free from microbial contamination and must maintain its sterility during its storage and use. o Easily drawn from syringe through gauge needle (syringeability) and is readily injected from syringe into the patient (injectability). Pharmaceutical Applications Of Suspensions Considered when: There is difficulty in swallowing solids by patients. Drug has poor solubility in aqueous medium, e.g. hydrocortisone and neomycin. If drug is degraded in aqueous medium, can synthesize an insoluble derivative and then suspend in a suitable vehicle to form a suspension. If contact time between soluble drug and dispersion medium need to be decreased - can supply as powder to be re-constituted before use. Ø Stability : 7 days at room temperature : 14 days refrigerated There is a need to mask taste - taste amplified if in solution than if in an insoluble form (suspension). E.g. Paediatric paracetamol: paediatric paracetamol elixir BP – as a suspension is more palatable and therefore more suitable for children. Topical application: Fluid preps e.g. Calamine Lotion BP designed to leave a light deposit of active agent on the skin after evaporation of the dispersion medium. Parenteral application: in order to control the rate of adsorption of the drug, by varying the size of the dispersed particles of the active agent, the duration of activity can be controlled. Vaccines (build up antibodies in the body) : For induction of immunity, as suspension. Consists of dispersions of killed microorganisms e.g Cholera Vaccine. Thus a prolonged antigenic stimulus is provided resulting in high antibody titre. X-Ray contrast media e.g. Barium sulphate – for examination of alimentary tract-oral or rectal administration. Aerosols also available as suspensions of active agent in a mixture of propellant. Formulation Of Suspensions Overview 1. Particle Size Control Ø Viscosity Modifiers 2. Wetting Agents Polysaccharides Water soluble cellulose 3. Flocculation or Hydrated silicates Deflocculation? Carboxymethylene (carbopol) Deflocculated suspension Colloidal silicone dioxide Flocculated suspension 4. Degree of Flocculation 6. Other Formulation Additives 5. Rheology of Suspension 1. Particle Size Control Drug to be suspended must be finely subdivided prior to formulation as rate of sedimentation of suspended particle can be decreased by reduction in size. Large particles > 5µm diameter have gritty texture – irritation if injected or instilled into eyes can occur. Ease of administration of parenteral suspension depends on particle size and shape. > 25µm diameter – can block the needle. Even if small particle size during manufacturing – crystal growth may occur on storage particularly if temperature fluctuation occurs. Reason: solubility of drug increase with increase temperature but on cooling - drug crystallizes out, e.g. paracetamol. 2. Wetting Agents Some insoluble solids maybe easily wetted by water and will disperse readily throughout aqueous phase with minimum agitation. Most however exhibit varying degrees of hydrophobicity. Clumping occurs. To ensure adequate wetting – interfacial tension between solid and liquid must be decreased so that adsorbed air is displaced from solid surfaces by the liquid. Examples of wetting agents: Surfactants: surfactants with HLB value of 7-9 will be suitable. The hydrophobic carbon chains would be adsorbed by the hydrophobic particle surfaces while the polar groups would project into the aqueous medium becoming hydrated. Wetting occurs due to a fall in interfacial tension between solid and liquid e.g. polysorbates (Tweens), Sorbitan esters (Spans). Hydrophilic colloids: will behave as protective colloids by coating the solid hydrophobic particles with a multimolecular layer. This imparts a hydrophilic character to the solid and thus promotes wetting. E.g. acacia, bentonite. Solvents: solvent will penetrate the loose agglomerates of powder displacing the air from the pores of the individual particles thus enabling wetting to occur by the dispersion medium e.g. glycerol. 3. Flocculation or Deflocculation? Deflocculated suspension Particles exist in suspension as discrete entities. Rate of sedimentation is slow, since it depends on the size of each unit. Sediment is formed slowly. Slow rate of settling prevents the entrapment of liquid within the sediment which thus becomes compacted. Sediment eventually becomes closely packed due to weight of upper layers of sedimenting material. Repulsive forces between particles are overcome and a hard cake is formed which is difficult to redisperse (caking). The suspension has a pleasing appearance since the suspended material remains suspended for a relatively long time. The supernatant also remains cloudy even when settling is apparent. Have the advantage of a slow sedimentation rate thus enabling a uniform dose to be taken from the container, but when settling does occur- difficult to redisperse. Flocculated suspension Particles form loose aggregates. Rate of sedimentation is high, since particles settle as flocs which is a collection of fine particles. Sediment is formed rapidly. Sediment is loosely packed and possesses a scaffold-like structure. Particles do not bond tightly to each other and a hard, dense cake does not form. Sediment is easy to redisperse so as to form the original suspensions. The suspension is somewhat unsightly, due to rapid sedimentation and the presence of an obvious, clear supernatant region. This can be minimized if the volume of the sediment is made large. Forms loose sediments which are easily redispersable but the sedimentation rate is fast and there is a danger of an inaccurate dose being administered and the product will look inelegant. A deflocculated suspension with sufficient high viscosity to prevent sedimentation would be an ideal situation. http://www.uobabylon.edu.iq/eprints/public ation_3_31242_6264.pdf 4. Degree of Flocculation NB for suspension to have correct degree of flocculation. Underflocculation = undesirable properties and overflocculation may be irreversible. Product will be inelegant and the viscosity high, resulting in difficult redispersion. Controlled flocculation achieved by combination of particle size control, use of electrolytes to control zeta potential and addition of polymers to enable cross linking to occur between particles. Examples of Flocculating Agents: Electrolytes: will alter the zeta potential of dispersed particles and if lowered sufficiently then flocculation may occur. (sodium salts of acetates, phosphates and citrates) Surfactants: ionic surfactant agents may also cause flocculation or deflocculation depending on the charge of the particles. Non ionic surfactants – because of linear configuration adsorb on to more than one particle thus forming a loose flocculated system. Polymeric flocculating agents: linear branched chain molecules form a gel like network within the system and become adsorbed onto the particle surfaces thus holding them in a flocculated state. If excessive blending-inhibits cross linking- can lead to deflocculated system (starch, alginates, cellulose derivatives, tragacanth etc.) 5. Rheology of Suspension Ideal pharmaceutical suspension must have a high apparent viscosity at low shear rates, therefore, particles settle very slowly on storage or remains permanently suspended. At high shear rates, e.g. shaking, suspension apparent viscosity should decrease, product can be easily poured from container. If for external use, spread easily but not so fluid that it runs off. Viscosity Modifiers 1. Polysaccharides A. Acacia gum (gum arabic) Used as a thickening agent – but not good Value as suspending agent – due to action as a protective colloid. Acacia mucilage – becomes acidic on storage due to enzyme activity – also has oxidase enzyme which causes deterioration of active substances which are susceptible to oxidation. But enzyme can be inactivated by heat. Sticky material – therefore not used in preps. For external use B. Tragacanth Forms viscous aqueous solutions Thixotropic and pseudoplastic properties - therefore better thickening agent than acacia. Used for internal and external preps Stable over pH 4-7.5 Viscosity affected by heat. Several grades are available. C. Alginates Made up of monomers: mannuronic acid, guluronic acid Not to be heated above 60°C. Depolymerization – loss in viscosity. Max viscosity at pH 5 - 9. Low pH – precipitation of alginic acid. Sodium alginate – most widely used. D. Starch Used in combination with tragacanth. 2. Water soluble cellulose A. Methylcellulose Semi-synthetic polysaccharide Several grades available. More stable in cold water, often dispersed in warm water, cooled, forms clear or opalescent viscous solution. Nonionic – therefore stable at pH 3-11 compatible B. Hyroxyethylcellulose Advantage – soluble in both hot and cold water and will not gel on heating. Similar properties to methylcellulose. C. Sodium carboxymethylcellulose Viscosity depends on the degree of polymerization. Anionic – therefore incomparable with polyvalent cations. Soluble in hot and cold water, stable pH5. Heat sterilization – decreases its viscosity. Preferred conc. for use is 1% D. Microcrystalline cellulose Readily disperses in water – but not soluble Forms a thixotropic gel Widely used suspending agent with between 8 and 11% sodium carboxymethylcellulose added to aid its dispersion and to act as a protective colloid. 3. Hydrated silicates Bentonite, magnesium aluminium silicate, hectorite. Readily hydrated – absorb up to 12 times the weight of water. Gels are thixotropic – therefore suspending agent. 4. Carboxymethylene (carbopol) Used in conc. Up to 5% for external application Some grades used internally When dispersed in water forms acidic low viscosity solutions, which when adjusted to pH 6-11 become highly viscous. 5. Colloidal silicone dioxide (Aerosil®) When dispersed in water – forms aggregate with 3D networks. Also used for thickening non-aqueous suspension. 6. Other Formulation Additives Buffers to maintain chemical stability, control tonicity or to ensure physiological compatibility. Density modifiers – so that disperse and continuous phases have same densities – sedimentation will not occur. Flavours, colorants, perfumes. Humectants – glycerol and propylene glycol – to prevent the product from drying out after application to skin. Preservatives. Sweetening agents. Manufacture of Suspensions Suitable size reduction equipment required for ensuring that powder to be suspended is suitably subdivided to ensure minimum sedimentation rate and adequate bioavailability. Small scale: powdered drug mixed with suspending agent and vehicle using mortar and pestle. Can include wetting agent at this stage to aid dispersion. Other ingredients should be dissolved in another portion of vehicle, mixed with concentrated suspension and made up to volume. Large scale: concentrated dispersion of suspending agent made first. Material added slowly to vehicle while mixing. Suitable mixers: impeller type of blenders or turbine mixers. 1. Physical Stability Assessed by measurement of the rate of sedimentation, the final volume or the height of sediment and the ease of redispersion. First two parameters – assessed by measuring total initial volume or height of suspension (Vo) and the volume or height of the sediment (V) By plotting the value of V/Vo against time for a series of trial formulations, the slope of the line can show the slowest rate of sedimentation. When the same ratio is constant - indicates that sedimentation has ceased. Alternatively the flocculation value can be used (Ratio of final volume of height of sediment and the value or height of the fully sedimented cake of the same system which has been deflocculated). Ease of redispersion can be assessed by simple agitation of the product in its container 2. Centrifugation Centrifugation would also be a suitable method for increasing the rate of sedimentation of a suspension, but this is accelerated testing - it is not possible to predict the behavior displayed under normal circumstances. Centrifugation may destroy the structure of the flocculated system, which may remain intact under normal storage conditions. Sediment formed would become tightly packed and difficult to redisperse whether or not initial suspension is flocculated or deflocculated. This method may however provide useful information of relative stabilities of a series of trial preparations. 3. Rheological Assessment Apparent viscosity measurements are used to assess physical stability, but the high shear rates may destroy the structure of the suspension. Very low shear rates can give an indication of the change in the structure of the system after various storage times. Maybe possible to combine the results from the sedimentation techniques with those from rheological assessments. Measurements of residual apparent viscosity after breaking down the structure of the suspension can be used as a routine quality control procedure after manufacture. 4. Temperature Cycling By exaggeration of temperature fluctuations that any product is subjected to under normal conditions – it is possible to compare physical stabilities of a series of suspensions. Cycling done-this is storage for several hours at a temperature greater than 40°C followed by freezing. Useful for assessment of crystal growth. Measurement of the particle size can indicate crystal growth changes → size measured microscopically, laser diffraction, coulter counter. Important to ensure that suspension is deflocculated to ensure that individual particle is measured rather than each floccule.

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