Aerosols PDF

AEROSOLS Prof Thiru Govender Discipline of Pharmaceutical Sciences Therapeutic Aerosols Definition: A fine dispersion of liquid or solid particles in a gas where the particle size is less than 50µm, as for example, a mist or smoke. Uses of Therapeutic Aerosols Preparation a...

AEROSOLS Prof Thiru Govender Discipline of Pharmaceutical Sciences Therapeutic Aerosols Definition: A fine dispersion of liquid or solid particles in a gas where the particle size is less than 50µm, as for example, a mist or smoke. Uses of Therapeutic Aerosols Preparation are for: § Application to external surfaces of the body. § Application to accessible body cavity e.g. mouth, nose. § Spray on protective films for wound and burn dressings. § Examples of actives: antiseptics, antibiotics, local anesthetics, dermatological steroids, bronchodilators. Advantages of Aerosols § Convenience, speed and ease of application. § Efficient dispersion of medicament. § Avoidance of manual contact with medication – therefore protects medication. § Immediate local application. § High concentration of medicament over a limited area is achieved. § Application is without manual contact with patient → therefore there is minimal irritation to painful area. § There is rapid response to medicament. § Controlled and uniform dosage dispensed via metered valves. § There is no contamination of product from environment. § Exclusion of light – protects photolabile drugs. § Absence of air – prevents oxidation. § Absence of H2O – prevents hydrolysis. § Drug administered by oral inhalation – no first pass effect.  Disadvantages § Cost → containers, valves, propellants and filling methods – more expensive. § Disposal may be difficult. § Cannot be subjected to heat → pressure build up. § If drug is insoluble in propellant → co-solvent emulsion or suspension systems required → leads to formulation difficulties. § Toxicity of propellant especially long-term use exists. § Refrigerant effect of highly volatile propellants → cause discomfort on injured skin. § Necessary to test formulation against all parts of container and valve. § Can be an environmental hazard. § Defective valve/spray system renders the product useless. Size Distribution ž Ideally aerosols should be ‘monodisperse’ ie. particles of the same size. ž Aerosols have a liquid/solid components of various sizes.  Aerodynamic Diameter ž Motion of the disperse phase in a gas stream depends on the size, shape and density of the aerosol particles. Variable which combines these three properties and is therefore used in the studies of deposition of aerosols in the human respiratory tract is the aerodynamic diameter. ž DA is the diameter of a sphere of unit density (1kg.dm-3 ) which has the same settling velocity as the particle in question. ž Used to determine deposition of aerosol in human respiratory tract.  Deposition of Aerosols in Respiratory Tract Occurs by the following mechanisms: Inertial Impaction Sedimentation Diffusion Interception Electrostatic Precipitation  Inertial Impaction § Particle carried in air stream has its own momentum → mass (inertia) x velocity. § When the gas stream encounters an obstacle or bend, the direction of gas flow changes. § The inertial force of the particle resists this change, causing it to move in its original direction → therefore a particle with high momentum may impact on the surface of the object in front of it, rather than follow the gas streamlines. § A very small fraction of the particles inhaled orally ( DA > 15µm) or inhaled nasally (DA > 10µm) will reach the trachea. § The combination of mass of the larger particles and the high flow velocity in the upper airways causes the particles to collide very easily in the pharynx. § Due to the successive branching of the air passages, the velocity of the gas gradually decreases from several ms-1 to less than 1mms-1 for the aveolar area. § Consequently, collision is less important mechanism for deposition in the lower airways.  Sedimentation § According to Stokes Law, the sedimentation speed of particles increases with the square of the aerodynamic diameter – sedimentation is therefore an important mechanism for deposition in the lower airways for those particles that have avoided collision up to that point ( 0.5µm < DA < 3µm ) § For particles with DA < 0.5µm, the sedimentation speed is so low that they will not sediment unless they can be kept in the lower airways for an extended period of time.  Diffusion § The bombardment of particles by atoms and molecules of the surrounding medium causes the particles of the aerosol to undergo random motion (Brownian). § Resultant effect on the particles is their directional movement from high to low colloidal concentration. § Consequently, particles diffuse from the aerosol cloud to walls of the respiratory tract.  Interception § Important for deposition of elongated particles in lower airways. Electrostatic Precipitation § Precipitation of charged aerosol particles by attraction to a surface of opposite charge is thought to be insignificant for drug aerosols in the respiratory tract.  Aerosol Systems: Two Types 1) Two Phase Systems § Liquid phase consists of the propellant or propellant mixture with the active principal in solution (emulsion → propellant emulsified into the aqueous phase = forms a foam). § Vapour phase consists of the vapour of the propellant(s) → since vapor pressure of the propellant is high, the contents exerts a pressure against the walls of the container. § When the valve is depressed, this internal pressure forces the liquid contents into the atmosphere where the propellant is instantly vapourized leaving a fine dispersion of the active principal. § If active is insoluble in propellant → use co- solvent → can affect vapour pressure. 2)Three Phase Systems § Solution of active in a suitable solvent which is immiscible with the propellant. § Three phases: 1. Propellant liquid phase 2. Solution liquid phase 3. Vapour phase § If propellant is lighter than the solution, the dip-tube must reach the bottom of the container. § If it is heavier, the dip-tube must be shortened so as to avoid spraying the propellant. § The two liquid phases can be emulsified § Propellant forms oil phase § o/w → produces foam § w/o → produces a coarse wet spray Propellants Propellants should have the following properties: 1) A vapour pressure of 1-7 kg.cm-2 at 21.1°C 2) Low toxicity 3) Inflammable and non-explosive 4) Odourless and colourless 5) Must be a good solvent 6) Must not cause irritation 7) Should be relatively cheap Classification of Propellants 1. Liquified Gases a) Fluorinated Hydrocarbons eg. fluoromethanes b) Hydrocarbons e.g. propane 2. Compressed Gases a) Insoluble Compressed Gases e.g. Nitrogen b) Soluble Compressed Gases e.g. nitrous oxide  Containers 1) Mechanical strength, chemical inertness and cost are criteria for selection of containers. 2) Glass protected with a plastic film against shattering is a suitable material for low pressure packages. 3) Stainless steel: expensive but can withstand high pressures and are virtually non-corrosive. 4) Tin plated steel: light material of low cost which can be made chemically non-reactive by suitable plastic coating. 5) Body of steel container consists of 3 separate pieces – made up of a cylindrical body, a top and a bottom which are joined. 6) Aluminium containers: may be two-piece or mono-bloc → be able to withstand high pressures. 7) Glass containers: moulded so as to accept different bottle valves → low pressures must be used. 8) Plastic containers: composed of acetal resins or polypropylene → able to withstand high pressures.  Valves, Dip Tubes & Actuators Type depends on formulation and application of product. Different valves used for sprays, foams and delivery of individual units. Achieved by “metering valves” → first stroke admits product into metering chamber – which stays enclosed. Constant volume of product then released from chamber. To ensure proper emptying of product - polyethylene/polypropylene dip tubes reach end of container and connected to valve.  Valve actuators shaped – to make application of product to desired body part easy. Two functions: §To depress the valve stem allowing the product and propellant to escape. §To break-up the stream of escaping product/propellant into the desired droplet size.  Basic Aerosol Formulation Depends on the solubility of the active principal in the propellant mixture: 1) The active is soluble in the propellant: - Active dissolved directly in propellant or mixture of propellant. - Combination of propellants used → relative proportions adjusted to produce the desired pressure. 2) The active is not soluble in the propellant but is soluble in a co-solvent: - Active can be dissolved in ethanol and added to the propellant mixture. -Ratio of co-solvent and propellant is very important. 3) The active is not soluble in the propellant or in a co-solvent but is soluble in H2O → two possibilities exist: a) Container filled with an aqueous solution of the active and the propellant is introduced → two liquid and one vapour phase produced. b) An emulsion is formed. 4) The active is an insoluble solid - Presented as a suspension in the propellant. - Particle size depends on size reduction of the active prior to formulation. - Recommended size → 5 -10 µm and not greater than 50 µm. - Particles should be thoroughly wetted by liquid phase and a dispersing agent may be required.  Factors Affecting Spray Characteristics 1) Viscosity - ↑ viscosity formulation → ↑ particle size of the spray, therefore it becomes coarse → get a wet spray. 2) Vapour pressure of propellants - ↑ vapour pressure → smaller particle size → leads to a fine spray. 3) Propellant product ratio → the greater the proportion of propellant in the formulation, the finer and drier the spray. 4) Presence of solvents – solvents and co-solvents may affect the pressure → which affect spray. 5) Temperature – change in vapour pressure occurs with a change in temperature.  Testing of Aerosols 1) Leakage → in-line leakage tests have been developed → individual containers are passed completely immersed through a bath of hot water so that the contents reach a temperature of 54.4°C → examined for leakage – bath is often illuminated for easier inspection – if contents are thermolabile → exempted from the test. 2) Internal pressure → measured by means of a pressure gauge with suitable adaptor to fit valve orifice. 3) Spray pattern → determined by internal pressure, viscosity and product-propellant ratio. Also examined visually. 4) Discharge rates → give an indication of the number of operations required to empty container. 5) Flammability → flame extension test is carried out. 6) Particle size analysis → Cascade impaction test done → based on particle impaction through a series of collection plates. Others: Phase Doppler Anemometry → measures scattering of laser beam by particles 7) Moisture determination → determined as it influences corrosion of metal and degradation of certain drugs. 8) Analysis of propellant mixture → carried out by gas-liquid chromatography.  Dry Powder Inhalers (DPI) e.g. Spinhaler ® / Handihaler ® ž Fine drug powder is mixed with an excipient (e.g. lactose) and supplied in a hard gelatin capsule. ž Particle size of excipient greater than particle size of drug → prevents excipient from entering airways. ž When capsule is opened (by capsule-piercing needle) prior to initial use, inhalation through the mouthpiece creates a turbulent airflow or spins the capsule so the powder is liberated and inhaled in the inspired air. Advantages of DPI’s 1) Hand-breath co-ordination not required 2) Environmentally benign 3) Possible to deliver proteins and peptides Disadvantages of DPI’s 1) More expensive than MDI’s 2) Requires frequent refilling 3) Loose powder can make device messy and cause coughing 4) Rely on inspiratory effect for aerosolization 5) Can vary markedly between patients and from day-to-day in any one patient  Capsule containing powder for inhalation Nebulisers Device used to convert aqueous solution of drug into a mist of fine particles for inhalation Two major types: Ultrasonic and Jet (Air–blast) Ultrasonic Nebuliser ž Electrically driven and work on the principal of a transducer which vibrates ultrasonically → cause drug in solution to break-up into small droplets. ž Advantage: quiet in use but requires an electric supply. May pose a problem with overheating. Jet (Air-blast) Nebuliser ž Consists of a compressed gas which enters a narrow tube immersed in the liquid to be aerosolized. ž The jet of pressurized gas creates an area of negative pressure → draws liquid up the tube ž When liquid reaches the area of negative pressure, it is broken up into droplets of gas ž Coarse droplets deposit on baffles and return to the liquid reservoir while the smaller droplets leave the device and can be inhaled as a mist, which is delivered to the patient via a mask or mouthpiece during normal tidal breathing.  Advantages of Nebuliser Therapy 1) Large doses of bronchodialator can be administered. 2) No hand-breath co-ordination required. 3) Problems of sensitivity to propellants is overcome with the use of isotonic vehicle. 4) The vehicle ( normal saline) is itself active in soothing the airways and liquifying secretions.