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The impact of surface energy of the drug on drug dissolution The constituent unit of a crystal at its surface exists in a different environment to the crystalline units in the bulk. Interactions occur between molecules on the particle surface and its environment, for example water or buffer during d...

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The impact of surface energy of the drug on drug dissolution The constituent unit of a crystal at its surface exists in a different environment to the crystalline units in the bulk. Interactions occur between molecules on the particle surface and its environment, for example water or buffer during dissolution. Solid surface energy is analogous to surface tension in liquid. Surface energy is an important phenomena for wetting, solubility, absorption, cohesion and adhesion. Surface energy has a dispersive SE component which involve Van der Waals interactions and a polar SE component which involves polar and hydrogen bonding. SE influences powders behaviour at interfaces with other solids, liquids and gases such as moisture sorption, dissolution, aggregation and gas adsorption. SE can be measured by contact angle in which polar and non-polar liquids are dropped on beds of compacted powder and the contact angle is measured. Dispersive and polar components can be then be determined. It may also be measured by inverse gas chromatography. The impact of drug powder surface area and porosity on drug dissolution Surface area has a significant impact on drug dissolution and is more important than particle size. Surface area is described per unit volume. The SA of non-porous particles depends on size and shape. The available SA of porous particles depends on the size of adsorbing molecules and pore size. The pore size distribution must also be considered as large molecules cannot penetrate into small pores. Porosity is of interest as the voids present in the powder can be as critical to the process than the material. The surfaces must be taken into account during processing due to liquid-solid, gas-solid and solid-solid interactions. Each particle has a particular mm² SA. the more surface that is available the more interaction the particle will have with the dissolution medium and therefore, the faster the dissolution will be. The available size of the pore must be large enough to allow access to the dissolution medium. Total SA can include the internal pores. Porosity is measured as the amount of air space present in the molecules and is measured by gas adsorption or mercury porosity. The influence of particle size and shape of the drug on powder flow When particles come into contact cohesive and adhesive forces caused by Van der Waals forces exist at the points of contact. These forces are quite small when the particles are large due to small surface area contact. Once the particle size is reduced, these forces increase due to increased surface area contact. In powders with particle size less than 100µm, strong cohesive forces prevent powder flow. Cohesion increases as particle shape departs from spherical. There is an acquisition of electric charge by frictional movement. Cohesive and adhesive forces oppose gravitational and momentum forces acting on particles during flow. Cohesion can increase the duration of contact potentially due to removal of adsorbed film. Powder handling problems such as aggregation or demixing can occur during flow. The powder uniformity can be undermined by segregation of different constituents during flow. Finer ingredients migrate to the bottom while larger ingredients roll or bounce along the top. The influence of powder mechanical strength on tablet compression Depending on the mechanical properties of a drug, powders will exhibit elastic, ductile or brittle behaviour. Solids when under applied stress such as compression, deform in different ways. Compression can result in permanent physical changes in powder properties such as fracture and plastic deformation as well as reversible changes such as elastic deformation.

The mechanical strength or particulate hardness will determine how the powder will deform into a solid. This will form tablets that can range from brittle to plastic. When enough compression stress is applied, all materials will fracture eventually. If the drug exhibits brittle mechanical properties it will experience little or no plastic deformation prior to fracture. If the drug exhibits ductile behaviour is will experience observable plastic deformation prior to fracture. If the drug is exhibits elastic mechanical properties it will deform under stress but recovers once removed. An imperfection in one plane of crystal can reduce mechanical strength and increase plastic deformation behaviour. If a crack is produced in a brittle tablet, stress concentrates at the tip of the crack. The stress wave from the tip of the crack initiates more fractures. Therefore compression can result in cracking of a brittle tablet. Tablet manufacturing stages: filling, compression and ejection A tablet is a solid pharmaceutical dosage form containing one or more drugs, prepared either from compression or moulding. Tablets are prepared by forcing particles into close proximity to each other by powder compression, which enables particles to cohere into a porous, solid specimen of defined geometry. Tablet manufacturing occurs in three stages. Filling is normally accomplished by the gravitational flow of the powder from a hopper via the die table into the die although some presses may use centrifugal die filling. The lower punch closes the die at the lower end. A glidant may be added during blending to enhance the flowability of the powder and hence filling. Colloidal silica is the most commonly used glidant today. The glidant particles are in a fine state and act on the surface of particles to reduce interparticulate friction. Glidants are frequently used in direct blend compaction. Compression takes place in the die by the action of the upper and lower punches by which the compressive force is applied. The upper punch descends and enters the die. The powder within the die is compressed. Compression is defined as the reduction in bulk volume by eliminating voids and bringing particles into closer contact. Due to the close proximity of particles, Van der Waals forces and hydrogen bonds are formed and thus a compact is formed. Compaction is defined as an increase in mechanical strength due to interparticulate interactions. During this stage, the lower punch can remain stationary or move upwards in the die. After maximum force has been applied, the upper punch leaves the die. A binder may be added to ensure that tablets can be formed with the required mechanical strength. For example, PVP or cellulose derivatives. During ejection the lower punch rises until its tip reaches the level of the top die and tablet is subsequently removed. Tablet ejection from the die results in additional stresses on the compact. A lubricant such as magnesium stearate may be added to reduce adhesion between the powder and the punch faces and thus prevent particles sticking to the punches which results in decreased ejection forces. Direct compression and blending Direct compression occurs in two steps (1) blending and (2) compression. Excipients are components of tablets that have a role other than the therapeutic effect. They are added to facilitate design of the tablet, to aid production and to aid patient compliance. Fillers are added to increase the bulk of the tablet. They are required for producing tablets with a potent API due to their low dose mass. They should have good flow and compression. Examples

include lactose, mannitol and microcrystalline cellulose. Disintegrants are added to promote tablet breakdown into smaller fragments in an aqueous environment. Disintegrants have different mechanisms of action. They can enhance the action of capillary forces by rapid uptake of aqueous liquids, swell when in contact with water and release gases and disrupt structure. Super disintegrants are designed to achieve good disintegrants at low concentrations such as croscarmellose sodium and crospovidone. Glidants are included in order to enhance powder flow. They are added in a fine state and act on the surface of particles. For example, colloidal silicon dioxide. A lubricant prevents powders sticking by forming a film on the surface of the dies and punches. Magnesium stearate is a widely used lubricant however, there have been reports of dissolution and hardness problems therefore a wetting agent may be added to overcome these effects. The surface area of solid lubricants is a critical parameter. [A rotary press (multi-station) or eccentric press (single-station). Discuss three stages.] The aim of blending is to achieve a uniform blend with low segregation tendency. Blenders used include IBC blenders, drum blenders and V blenders. During the mixing process powder beds expand, therefore the blender volume should be < 75%. Three dimensional shear forces result in random turbulent movement of powder. Cohesive forces cause the powder to move causing agglomerates to form and resulting in poor mixing. The duration and number of rotations are more important than speed. The duration of mixing should be long to achieve a random mix. Blend segregation can occur for many reasons. Demixing occurs due to differences in particle size, density and shape. In order to achieve mixing, particle size, shape and density of each component should be similar, i.e. drug and diluent. Percolation segregation occurs when small particles fall into voids formed by larger particles during standing. Trajectory segregation is caused particles set in motion during mixing and kinetic energy. Larger particles give larger energies and thus travel greater distances. Densification segregation occurs when the mass is subjected to vibration. Smaller particles move beneath and support the larger particles. Segregation of the blend can occur during blending, storage, flow, transfer between containers or tabletting. Discuss problems tabletting problems and how they may be overcome Tablet dosage. Dosage variation outside the specified limits is caused by improper mixing and segregation of the blend. This may be overcome by increasing or decreasing mixing and correcting powder properties. Tablet weight. Weight variation outside specified limits. This is due to poor or erratic powder flow or flooding, powder properties must be corrected. The particle size range may be too wide and thus must be narrowed to avoid excessive fines. The particle size may be unsuitable for the die, therefore the particle size must be adjusted to suit die. Tablet hardness. Insufficient compression causes low tablet hardness, therefore the compression force must be increased and compression speed must be reduced. Hardness variability is due to uneven die filling, powder properties must be corrected. Sometimes,

hardness increases with time caused by water interacting with the API and excipients, to overcome this the moisture content in granules must be optimised. Tablet appearance. Punch filming or sticking is occurs for many reasons. Perhaps due to poor finish or worn tooling. Tooling must be polished, refaced or replaced. Embossing letters such as A, B, P or R should be avoided. The punch concavity may be too great and should be reduced or flatter punches to be used. Low melting point ingredient which thus should be replaced. Inadequate lubrication, a lubricant should be added. Tablets are too soft, compression force should be increased. Discuss pharmaceutical processes which include a drying step Drying is defined as the vaporisation and removal of water or another fluid from a solution, suspension or other solid-liquid mixture to form a dry solid by supplying latent heat. Drying involves a phase change of liquid to vapour. Most pharmaceutical materials contain residual water which may vary with the temperature and humidity of the ambient air to which they are exposed. Drying is an important operation in primary pharmaceutical manufacture as it is usually the last stage of manufacturing before packaging. It is important that the residual moisture is rendered low to prevent degradation of the product during storage and ensure free-flowing powders during use. It is also important in secondary manufacture following wet granulation. Hence, stability, flow properties and compaction are all influenced by residual moisture and thus drying. Discuss the factors that influence the rate of drying Environmental conditions such as temperature and humidity. At low temperature, only a few water molecules have sufficient energy to escape from the surface of the solid material by overcoming molecular attractions. A rise in temperature results in molecules having greater kinetic energy, allowing them to escape into the vapour phase. Partial pressure (concentration) of water vapour at the solid surface compared to the drying air. Moisture vapour will diffuse from the solid surface to air driven by a concentration gradient. Particle size and available surface area of the solid. The smaller the particle size, the greater the surface area and thus greater exposure to the drying air which increases the drying rate. Discuss the types of dryers used in pharmaceutical processing Conduction dryers include vacuum tray, rotary cone, paddle and tumble dryers. The wet solid is in contact with a heated surface. A tray dryer is a fixed bed convection dryer. For the most efficient drying air must be circulated in a fixed direction. The material to be dried should be spread as thinly as possible directly on shelves or on trays. The rate of drying is controlled by circulating air humidity, thickness of laminar air layer above the material and thickness of bed material to be dried. A fluidised bed dryer is a dynamic convection dryer which uses a technique called fluidisation of material. Material to be dried is place in a vessels with a perforated base which allows the passage of air. As the air velocity increases the particles are eventually suspended in the air. There is increased contact between the hot air and particles. Fluidised bed drying is very advantageous as it can reduce drying time to 20 - 30 minutes and is suitable for thermolabile materials as well as a free flowing powder being produced.

Radiation drying such as IR or microwave involves heat transmission by radiation travelling through space and when it reaches an absorbing body it appears as heat, therefore it does not require a medium for transport. IR is usually a heated element 500-1000K. Heat is absorbed rapidly, but does not penetrate far into the wet mass. Surface layers are dry quickly. Microwaves are produced by a magnetron and penetrate much better. Heating is unidrom and can be scaled up to large size batches 800kg. However, operators must be shielded. Discuss milling in terms of particle size reduction Comminution is the generic term for size reduction while milling is commonly used to describe many types of size reduction. Milling improves drug dissolution and solubility. A hammer mill uses the impact method and is used for powders and granules. A cone mill and pin mill use the impact and attrition method and are used for powders and granules. The screen thickness can influence product particle size. The equipment selected depends on starting material characteristics such as melting point, weakness in the solid, bond strength, particle size distribution, texture, flammability and reactivity in air. Discuss why some solid dosage forms may be coated Some solid dosage forms are coated for a number of reasons. To increase patient compliance by masking an odour or an unpalatable API as wells as increasing swallowability. To enhance the elegance and glossy appearance of the tablet core. To avoid side effects caused by the API such as gastric irritation by applying an enteric polymer coat. To avoid incompatibility of API by physical separation of incompatible substances into the core and coat the tablet. To allow identification of the product. Discuss the film coating in terms of sustained release Coating can be non-functional for aesthetic reasons or functional, used for sustained release or enteric coating. Non-functional polymers include cellulose esters such as HPMC, glycols and acrylics. Sustained release can be divided into three. Matrix or monolith devices, the drug is dispersed as particles in a compressed mixture or granule containing a sustained releasing polymer. Reservoir devices in which the drug is surrounded by a sustained releasing polymer. Combination of reservoir and monolith devices in which the drug is present in a matrix system and surrounded by a rate controlling membrane. Functional polymers include phthalates such as CAP and PVAP, methacrylic and shellac. Sustained release application relies on their ability to swell and being permeable to dissolved drug and water. It is influenced by level of coating, viscosity and molecular weight of polymer. Plasticisers may be added in order to increase plasticity i.e. render the polymer more flexible. Plasticisers are low molecular weight organic solvents with high boiling points. They have some similar FGs to enhance miscibility with the polymer. They reduce cohesive forces and increase water permeability. Examples include polyols, organic esters and oils/glycerides. Pigments are used for product identity, protection against light, modify gas permeability and decrease risk of counterfeiting. An aqueous system is always the first choice of solvent.

Discuss the equipment employed in the coating process A perforated coating pan, coating is sprayed as a fine mist due to hydraulic pressure. It must be ensured that the cores can withstand the tumbling motion. Movement of the cores in the pan should be rolling motion and not sliding or cascading. Optimum movement is controlled by speed pan rotation and baffles. Fluidised bed coating. The cores are placed in a vessel container with a perforated base to allow passage of air. Cores are suspended in an air stream and therefore, are not in contact with each other during spraying and drying. Discuss problems that may arise during coating Chipping occurs due to high pan speed or a friable tablet core. Therefore, the pan speed or friability of the cores must be reduced. An orange peel appearance is due to high atomisation pressure with high solution rates combined with tablet rubbing. Atomisation and solution rates must be reduced. Dusty and uneven coating is a results from the distance between the guns and bed being too great, inlet temperature being too high, air volume being too high or rate of application being too low. Picking and sticking occurs due to over wetting, solution application rate must be reduced and distance between guns and bed must be increased. Under drying also is a cause and inlet temperature and volume of air flow must be increased. Capping originates in compression but is not seen until coating. Twinning occurs due to tablet shape or the relative motion of tablets in pan is suboptimal.

Discuss capsule manufacturing as a pharmaceutical process There are two types of pharmaceutical capsules, hard gelatin caps which are two-pieced and soft gelatin caps which are one-pieced.Capsules have many advantages for oral drug delivery. Capsules can increase patient compliance as they can mask the odour or unpalatable taste of an API. They have better bioavailability and easier method of formulation compared to tablets. The drug is given reasonable protection from air, moisture and light. The exact dose may dispensed for an individual patient. They are capable of controlled release and have easy product identity. However, there are some disadvantages which include automatic capsule filling machines have an output only ⅕ of tablet press speed. If the drug is rapidly released it may cause gastric irritation due to a high local concentration. Capsules may adhere to the oesophagus. There are two types of pharmaceutical capsules, hard gelatin caps which are two-pieced and soft gelatin caps which are one-pieced. Gelatin is non-toxic, readily soluble in biological fluids at body temperature and is not pH dependent. It is prepared by hydrolysis of collagen. The fill for hard capsules can be dry solids such as powders, pellets and granules, semisolids such as thermosoftening, thixotropic mixtures and paste or liquids such as nonaqueous liquids. However, there are limitations in that the fill must not react with the shell material, not contain a high level of free moisture which result in shell softening and the volume of the unit dose must not exceed ...