Pharmaceutics Suspension

PHARMACEUTICS SUSPENSION 2021 Definitions • Suspension is a dispersion of a solid material (the • • • • dispersed phase) in a liquid (the continuous phase) without reference to the particle size of the solid material. Colloidal suspension: with a particle size range of up to about 1 μm Coarse dispersion: with larger particles. Pharmaceutical suspensions: fall across the borderline between colloidal and coarse dispersions, with solid particles generally in the range of 0.1 to 10 μm. Suspensions are not optically clear and will appear cloudy unless the size of the particles is within the colloidal range. Cont. • In the ideal suspension, the particles of the solid material are mono-dispersed spheres and are evenly suspended in three dimensions throughout the vehicle and remain so even after prolonged periods of time. Pharmaceutical Applications of Suspensions • Insoluble or poorly soluble drugs in a suitable solvents • People having difficulty in swallowing solid dosage forms. • Overcome unacceptable taste of drugs that is difficult to mask when prepared as a solution • Rate of dissolution and rate of absorption is usually faster in oral suspension than when delivered as a solid dosage form. But slower than the rate from solution. • Insoluble forms of drug may prolong its action by preventing rapid degradation of the drug in the presence of water. Cont. • If the drug is unstable when in contact with the vehicle, suspensions can be prepared prior to handling out to the patient • Drugs which degrade in aqueous solution can be suspended in non-aqueous phase (e.g. Tetracycline HCl is suspended in coconut oil for ophthalmic use). • Intramuscular, intra-articular or subcutaneous injections are formulated as suspensions to prolong the release of the drug (depot therapy). Pharmaceutical uses of suspensions • • • • • • • Used for: Oral administration. Inhalation Topical application Ophthalmic preparations Parenteral administration Aerosols Properties of colloids 1. Size distribution: The molecular weight or particle size is an average value. In the light-scattering method for the measurement of particle size, larger particles produce greater scattering. 2. Shape: Many colloidal systems contain spherical particles. polymers and macromolecules form random coils in aqueous solution. Cont. Optical properties: 1. Light scattering: When a beam of light is passed through a colloidal sol. some of the light may be absorbed, some is scattered and the remainder is transmitted undisturbed through the sample. it is possible to calculate the molecular weight and particles size by measuring the scattered light, at an angle (usually 90°) relative to the incident beam. 2. Electron microscopy: Is used to observe the size, shape and structure of colloidal particles. The success of the electron microscope is due to its high resolving power. The ‘electrical double layer’ theory • Hydrophobic drugs once dispersed as solid particles in an aqueous environment, they will acquire a charge. • The charge produced is not as a result of ionization of the drug, rather it is due to the ionization of water. • Some of the hydroxide ions will then collect on solid surfaces within the aqueous dispersion and give an apparent negative charge on these surfaces. • Gradation of charge occurs in two stages, giving rise to two ‘layers’ of charge surrounding the particle: electrical double layer. The ‘electrical double layer’ theory Factors affecting the electrical double layer • Ionic materials (high and low concentration). • Surface active agents. Particle movements in suspensions • Brownian movement • Sedimentation • Flocculation status of the suspension: Deflocculated systems behave as individual small particles, whilst flocculated systems behave as individual large particles with a porous structure. Brownian motion: random collisions with the molecules of the dispersion medium with the result that each particle have an irregular and complicated zigzag path. Diffusion: As a result of Brownian motion, colloidal particles spontaneously diffuse from a region of higher concentration to one of lower concentration. Brownian motion and diffusion • The result of Brownian motion is diffusion of the particles throughout the medium, from an area of high concentration to one of low concentration. • Diffusion result in more homogeneous distribution of the particles throughout the system. • It can be described by the Stokes-Einstein diffusion equation • It can be seen that reducing the particle size will increase the diffusion constant and, conversely, increasing the particle size will reduce it. Sedimentation • Sedimentation is the downward movement of particles under gravity, and is observed for particles with radii of approximately 0.5 μm and greater. • Sedimentation is described by Stokes’ sedimentation equation • where v is the sedimentation velocity, a and d are the particle radius • • • • and diameter respectively, g is the acceleration due to gravity, ρ and ρ0 are the densities of the particles and the medium respectively, and η is the viscosity of the medium. It shows that reducing the particle size will reduce the sedimentation rate. Both flocculated and deflocculated systems will show sedimentation. flocculated systems will settle quickly whereas deflocculated systems will settle more slowly. Increasing the viscosity of the medium will reduce sedimentation. Controlling particulate movement in suspensions 1. a , the radius of the particle: Reducing particle size will increase diffusion and reduce sedimentation, with a larger effect on the sedimentation rate. 2. ρ, the density of the particles: Particles are generally denser than the medium in which they are dispersed, and the greater the density difference the faster the sedimentation rate. • Reducing the particle density by changing crystallization methods is possible, but this will result in an increased particle size or an increased number of particles. Cont. 3. ρo, the density of the medium. • Reducing the density difference between the particles and the medium by increasing the density of the medium will lead to a reduction in sedimentation rate • Addition of materials such as dextrose or some polymers will raise the density of the product sufficiently to reduce the observed sedimentation. 4. η, the viscosity of the medium. • Increasing the viscosity of the medium will reduce diffusion of the particles. • An increased viscosity will also reduce the particulate sedimentation rate. Cont. 5. T, temperature (in Kelvin): • Increasing the temperature will lead to an increase in the diffusion constant and greater particle mobility. • The viscosity of a given substance will change with temperature, affecting both diffusion and sedimentation. Measuring particle movement • A known volume of the suspension with the solid particles dispersed is placed in a graduated cylinder and left to stand, allowing sedimentation to occur. • At certain time intervals, the volume of sediment is measured and the sedimentation volume ratio, F, calculated. • Where F is the sedimentation rate. • Vo is the initial volume of suspension before settling • Vf is the final volume of sediment. Sedimentation of a flocculated suspension Sedimentation of a flocculated suspension • In a flocculated system, the particles are arranged in loose aggregates or floccules, which behave as large, porous individual particles. • These floccules will begin to sediment quickly, generally within a period of minutes, leaving a clear supernatant, and sedimentation will reach a maximum within a few hours or days. • The sediment formed is loose and fluffy and can be easily redispersed by shaking. • A high volume of sediment is observed, with calculated values of the sedimentation volume ratio, F, being up to 0.6. Sedimentation of a deflocculated suspension Sedimentation of a deflocculated suspension • Sedimentation takes some time, measured in days and • • • • • weeks rather than minutes. In the initial stages of sedimentation, a small amount of compact sediment is observed at the base of the cylinder, with no, or limited clear supernatant being observed. The volume of sediment and the volume of clear supernatant both increase. The sediment formed is dense and compacted, described as being ‘caked’. Redispersion of the caked sediment is difficult. A low final volume of sediment is observed, with calculated values of the sedimentation volume ratio, F, being as low as 0.1. What is the desired sedimentation pattern? Two factors need to be considered: 1. speed of sedimentation 2. reversibility. • A deflocculated system with no or minimal sedimentation, which will require greater viscosity and density adjustments vs. a flocculated system with controlled slow sedimentation which will require less viscosity and density adjustments than for a deflocculated system and allow easy re-dispersion of particles upon shaking??? Dispersibility issues – surface wetting • Wettability is the ability of a liquid to spread across a solid surface. • In order to reduce the surface tension, the solid particles are clump together….inhomogeneous suspension. • A reduction in the surface tension between the particles and water is necessary to improve the wettability of the solvent over the solid. • This is usually produced by the addition of a surfactant, below its CMC, to the medium. Cont. Contact angle measurement: To assess wettability and dispersion problems. • Generally, contact angle measurement should be used as a guide only, with values less than 90° indicating reasonable wetting would be expected and values greater than 90° suggesting that problems are likely to be observed during dispersion. Dissolution issues • Drugs are formulated as suspensions for oral delivery because they show limited aqueous solubility related to their target dose. • However, in order for the drug to be absorbed orally, it must be dissolved within the gastrointestinal tract and so dissolution behaviour must be considered. • The Noyes-Whitney equation • Increasing the surface area, whilst keeping the total quantity of drug the same, will increase the dissolution rate of the drug and promote oral bioavailability. • Effect on flocculation behaviour??? Ostwald ripening • Where small particles in suspension seem to disappear and large particles grow after repeated temperature changes; • If the suspension is exposed to a higher temperature, then the solubility of the drug will increase . If the suspension is then placed in lower temperature conditions, the solubility of the drug will decrease to below the concentration now in solution, Some of the ‘excess’ drug will precipitate out and will do so preferentially onto the larger particles, with their greater surface area • The smaller particles may have grown slightly, but the larger particles will have grown more. Ostwald ripening General suspension formulation considerations 1. Solubility: the solubility profile of the drug as a function of temperature needs to be established. • The drug needs to remain in the same dispersion state, throughout the shelf-life of the product, • Ostwald ripening must be avoided • An ideal solubility profile is flat, that is there is minimal change in the equilibrium solubility of the drug with temperature. • Usually, the lower the aqueous solubility, the greater the chance of a flat profile being obtained. • If the drug has some aqueous solubility, then the solubility of the drug need to be suppressed, to maintain the suspended nature of the drug: anti-solvent, pH, pro-drug Cont. 2. Formulation excipients: • Flavours ,sweeteners and colours • Antimicrobial preservatives: sorbic acid, benzoic acid, parabens, chloroform, sucrose, benzalkonium chloride and parabens. Their effect on viscosity and flocculation system?? • Buffers: Buffers may be used in suspension formulations if a particular pH is required due to the route of administration, or if the solubility of the drug is suppressed by formulating at a particular pH. • A buffer system will contribute charges to the formulation, which will affect the flocculation behaviour of the suspension • The use of a buffer may also affect the ionization state of other components, such as preservatives. Cont. 2. Formulation excipients: • Chemical stabilizers: Antioxidants, such as ascorbic acid, used at concentrations of 0.2% w/v and sodium metabisulfate, used at levels of about 0.1% w/ v and chelators such as ethylene diamine tetra-acetic acid (EDTA). Cont. 2. Formulation excipients: • Density modifiers : Increasing the density of the suspension formulation help to reduce the sedimentation rate of the dispersed particles by the addition of a sugar such as dextrose or sucrose. • Viscosity modifiers: (suspending agents) as they will reduce the sedimentation of the particles and keep them suspended for longer by the addition of polymeric materials or inorganic materials. Cont. • Viscosity modifiers: 1. Cellulose: methyl cellulose MC, hydroxypropylcellulose HPC, hydroxypropyl methylcellulose HPMC, Carboxymethylcellulose CMC • They are water-soluble and will not interfere with the flocculation behaviour of the particles. Cont. 2. Alginic acid, a polymer derived from seaweed • It consists of β-D-mannuronic acid, and α-L-guluronic acid joined via a (1→4) link • Alginic acid is easily ionized and is used as the sodium salt. • Addition of alginic acid, either as the he intact acid or as the sodium salt, will extract Ca2+ ions from the Surroundings. • This will change the flocculation behaviour of the particles and increase the viscosity of the system. Cont. 3. Clays: are water-insoluble inorganic materials that, when dispersed in water, will absorb water into their structure • A clay suspension shows some rheological structuring and will retard the sedimentation of other materials suspended with it. 4. Gum Arabic: is composed of a complex mixture of saccharides and glycoproteins. • Once dissolved in water, gum arabic forms a viscous solution which can be used to retard sedimentation of suspended materials. • Tragacanth is a complex polysaccharide mixture. Cont. 5. Wetting agents • Wetting agents are used to improve the flow of the liquid vehicle across the particle surface which improves the homogeneity of distribution of the drug particles throughout the formulation by reducing the interfacial tension between the solid particle and liquid medium • Wetting agents are surfactants below their critical micelle concentration (CMC). • Surfactants will localize on the surface of the particle, affecting the surface charge, ψ0 and an indirect effect on the thickness of the diffuse layer, resulting in alteration of the flocculation behaviour of the system. Cont. 6. Flocculation modifiers: • Are ionic materials which ionize once in solution in the suspension medium, e.g. sodium chloride (NaCl) . • Its function is to adjust the flocculation status of the particles to that which is intended. • The quantity of flocculation modifier required must be determined last. • The effect of the flocculation modifier on the flocculation behaviour of the particles is dependent on the ionic strength in solution. • A multivalent salt (e.g. calcium chloride, CaCl2) will have a greater effect than a monovalent salt (e.g. NaCl). Cont. 2. Formulation excipients: • Colloids stabilizers: A colloid stabilizer is a material which will prevent or retard the coalescence of particles suspended in a medium. e.g. surfactants. Stability considerations for suspensions • The drug must remain chemically stable over the intended shelf-life of the product. • Chemical preservatives • The effect of temperature on the chemical stability of the drug. • Sedimentation should ideally be kept to a minimum and where sedimentation is permitted or unavoidable, easy redispersion of the sediment is necessary. • Visual assessment of sediment redispersion on shaking is Useful. • Assessing the particle size distribution and drug content of samples taken from the top, middle and bottom of the container. Manufacturing considerations • Poor initial dispersion will lead to swift coagulation and sedimentation. • Suspensions require large quantities of pharmaceutical grade water. • Packaging of the suspension into containers will require a stirred hopper to minimize settling during the packaging process. Rheology • Newtonian fluid: • Simple fluid obeys Newtonian Law are called Newtonian fluid where the rate of flow (ϒ ) was directly proportional to the applied stress (σ). • Newtonian law can be expressed as Ƞ= σ/ ϒ • The Ƞ is the coefficient of the dynamic viscosity. Rheological properties of suspensions • Non-Newtonian fluid: • Plastic (Bingham bodies) • Pseudoplastic • Dilatant • Plastic material does not flow until a value of shear stress has been exceeded Rheological properties of suspensions • Flocculated suspensions tend to exhibit plastic or pseudoplastic flow, depending on concentration, while concentrated deflocculated dispersions tend to be dilatant. • This means that the apparent viscosity of flocculated suspensions is relatively high when the applied shearing stress is low, but it decreases as the applied stress increases and the attractive forces producing the flocculation are overcome. Cont. • The apparent viscosity of a concentrated deflocculated suspension is low at low shearing stress, but increases as the applied stress increases. • This effect is due to the electrical repulsion that occurs when the charged particles are forced close together causing the particles to rebound, creating voids into which the liquid flows, leaving other parts of the dispersion dry.