Harit Desai, MD

• Department of Medicine
• New York Medical College
• Westchester Medical Center
• Valhalla, NY

When the cell concentration is below this value virus removal programs purchase nitrofurantoin 50 mg line, it is necessary to pass a known quantity of the liquid antibiotic resistant gonorrhea 2015 nitrofurantoin 100 mg buy on-line, typically 10 mL to 100 mL or even more virus not alive nitrofurantoin 100 mg purchase overnight delivery, depending on the dosage form or specific product in question virus kids ers order cheapest nitrofurantoin, through 242 Very low concentrations of microorganisms in aqueous solutions antibiotic resistance yeast order 50 mg nitrofurantoin otc. It is necessary to suspend an insoluble solid in a medium that will permit uniform dispersion and adequate wetting of the suspended material. Nutrient broth, peptone water or a buffered salt solution is frequently used, and a low concentration of a surfactant may be incorporated to promote wetting. Suspension in distilled water alone carries the risk of osmotic damage to sensitive cells, with a consequently low count; for this reason, it is best avoided. Having obtained the suspension, there are two options available depending on the nature and concentration of the suspended material. The first is to remove a sample of the continuously mixed suspension, dilute it if necessary, and plate it in or on a suitable medium by a pour-plate or spreadplate method. The alternative is to dislodge the microbial cells from the solid to which they are attached, allow the solid to sediment out and then sample the supernatant. Methods of removal include vigorous manual shaking, the use of a vortex mixer or the use of equipment designed for the purpose. The use of ultrasonics to dislodge the cells carries the risk of damage to , or lysis of, the cells themselves. The alternative strategy of sampling the supernatant involves the assumption that all the cells have been removed from the solid but this would have to be confirmed by control (validation) experiments in which a known quantity of similar organisms was artificially dried onto sterile samples of the material. The second method also relies on the solid sedimenting sufficiently rapidly for it to be separated from the bacteria in aqueous suspension above it. If all or part of the sample has a particle size similar to that of bacteria, yeasts or mould spores, i. Alternatively, the oil may be dissolved in a sterile, nontoxic solvent and passed through a membrane filter. Isopropyl myristate, for example, is recommended in pharmacopoeial sterility testing procedures as a solvent for anhydrous materials but it may kill a significant fraction of the cells of some sensitive species, even during an exposure period of only a few minutes. Oil-in-water emulsions do not usually represent a problem because they are miscible with water and thus are easily diluted. Water-in-oil creams, however, are not miscible and cannot be plated directly because bacteria may remain trapped in a water droplet suspended in a layer of oil on the agar surface. Such bacteria may not form colonies because the diffusion of nutrients through the oil would be inadequate. These creams are best diluted, dispersed in an aqueous medium and membrane filtered or converted to an oil-in-water type, and then counted by normal plating methods. Dilution and emulsification of the cream in broth containing Lubrol W, polysorbate 80 or Triton X-100 is probably the best procedure, although the addition of approximately 0. These materials Detection of specific hazardous organisms In addition to placing limits on the maximum concentration of microorganisms that is acceptable in different materials, pharmacopoeias usually specify certain organisms that must not be present at all. In practice, this means that detection methods which are described in the pharmacopoeia must be applied to a known weight of material (typically 1 g to 10 g), and the sample passes the test if, on the culture plates, no organisms arise that conform to the standard textbook descriptions of those to be excluded. Commercially available identification kits or specific supplementary biochemical tests may also be used to confirm the identity of any isolates having the typical appearance of the target organisms. The PhEur used to recommend appropriate supplementary tests but these have been removed from the current edition, not because of a 243 are usually not heavily contaminated because they are anhydrous and microorganisms will not multiply without water. Thus the microorganisms contained in oily products have usually arisen by contamination from the atmosphere, from equipment used for manufacture and from storage vessels. To perform a viable count, the oil sample must be emulsified or solubilized without the aid of excessive heat or any other agent that might kill the cells. An oil-in-water emulsion must be produced using a suitable surfactant; nonionic emulsifiers generally have little antimicrobial activity. The proportion of surfactant to be used must be determined experimentally and validation experiments must be conducted to confirm that the surfactant is not toxic to the species that typically arise as contaminants of the sample in question; Millar (2000) has described the use of up to 5 g of polysorbate 80 added to a 10 g sample. Not part of European Pharmacopoeia (European Pharmacopoeia Commission, 2017) procedures. In addition, the PhEur describes a test for clostridia, but this is unlikely to be applied to any material other than mined minerals. The five organisms common to both pharmacopoeias are the subject of these tests primarily because of their potential to cause infections. However, they may also represent common contaminants of the products to which the tests are applied, or their presence may be indicative of the quality of the raw material or finished manufactured product. In 244 addition, there is a requirement that products for use in the mouth, nose, or ears or on the skin should be free of both P. These schemes are described in more detail elsewhere, together with photographs of the typical appearance of the organisms in question (Hodges, 2000). Microbiological assays of B-group vitamins employ similar techniques to those used in turbidimetric assays of antibiotics (see earlier in this chapter). The extent of bacterial growth in the medium is thus directly proportional to the amount of reference standard or test vitamin added. It is important to select an assay organism that has an absolute requirement for the substance in question and is unable to obtain it by metabolism of other medium components; species of Lactobacillus are often used for this purpose. Sterile products Sterile products must, by definition, be free of viable microorganisms, and it is important to understand that this is an absolute requirement. Thus, the presence of one single surviving microbial cell is sufficient to render the product nonsterile. There is not a level of survivors which is so small as to be regarded as negligible and therefore acceptable. The principal component of microbiological quality assurance which has traditionally been applied to sterile products is, of course, the test for sterility itself. In essence, this is quite simple: a sample of the material to be tested is added to culture medium, which is incubated and then examined for signs of microbial growth. If growth occurs, the assumption is made that the contamination arose from the sample, which consequently fails the test. However, the limitations of this simplistic approach became more widely recognized in the second half of the 20th century, and there was an increasing awareness of the fact that contaminated products could pass the test and sterile ones apparently fail it (because of contamination introduced during the testing procedure itself). For these reasons the sterility test alone could no longer be relied on to provide an assurance of sterility, and that assurance is now derived from a strict adherence to high quality standards throughout the manufacturing process. These encompass: · Adoption of the highest possible specifications for the microbiological quality of the raw materials. The rationale here is that sterilization processes are more likely to be effective when the levels of microorganisms to be killed or removed (bioburdens) are as low as possible to begin with. Procedures used to determine bioburdens are described in Chapter 13 and earlier in this chapter. Initial validation seeks to demonstrate that adequate sterilizing conditions are achieved throughout the load, and entails extensive testing with thermocouples, radiation dosimeters and biological indicators (see later) as appropriate. The pharmacopoeias and regulatory authorities require a sterility assurance level for terminally sterilized products of 10-6 or better. This means that the probability of nonsterility in an item selected at random from a batch should be no more than 1 in 1 million. This sterility assurance level may be demonstrated in the case of some terminally sterilized products simply by reference to data derived from bioburdens, environmental monitoring and in-process monitoring of the sterilization procedure itself. Sterilization monitoring Sterilization processes may be monitored physically, chemically or biologically (Denyer et al. Physical methods are exemplified by thermocouples, which are routinely incorporated at different locations within an autoclave load, whereas chemical indicators usually exhibit a colour change after exposure to a heat sterilization process. Biological indicators consist of preparations of spores of the Bacillus or Geobacillus species that exhibits the greatest degree of resistance to the sterilizing agent in question. Spores of Geobacillus stearothermophilus (often still indexed in the pharmaceutical literature under its former name of Bacillus stearothermophilus) are used to monitor autoclaves and gaseous hydrogen peroxide or peracetic acid sterilization processes, whereas Bacillus atrophaeus is the organism normally employed for dry heat, ethylene oxide and low-temperature steam­formaldehyde methods; Bacillus pumilus is used in radiation sterilization procedures. Such biological indicators are regularly employed for validation of a sterilization process which is under development for a new product, or when a new autoclave is being commissioned; they are not normally used for routine monitoring during product manufacture. Spores possess the advantage that they are relatively easy to produce, purify and dry onto an inert carrier, which is frequently an absorbent paper strip or disc, or a plastic or metal support. Spore resistance to the sterilizing agent must be carefully controlled, and so rigorous standardization of production processes followed by observance of correct storage conditions and expiry dates is essential. Tests for sterility It is sufficient here to repeat that the test is really one for demonstrating the absence of gross contamination with readily grown microorganisms, and is not capable of affording a guarantee of sterility in any sample that passes the test. The experimental details of these procedures are described in the PhEur (European Pharmacopoeia Commission, 2017). This section is therefore restricted to an account of the major features of the test and a more detailed consideration of those practical aspects that are important or problematical. It is obviously important that materials to be tested for sterility are not subject to contamination from the operator or the environment during the course of the test. For this reason, it is essential that sterility tests are conducted in adequate laboratory facilities by competent and experienced personnel. Clearly, the consequences of recording an incorrect sterility result may be very severe. If a material which was really sterile were to fail the test, it would need to be resterilized or, more probably, discarded. If, on the other hand, a contaminated batch were to pass a test for sterility and be released for use, this would 246 obviously represent a significant health hazard. For these reasons, sterility testing procedures have improved significantly in recent years and failures are now viewed very seriously by the regulatory authorities. If a product does fail, it means either that the item in question is really contaminated, in which case the manufacturing procedures are seriously inadequate, or that the item is in fact sterile but the testing procedure is at fault. Sterility tests may be conducted in clean rooms or laminar flow cabinets which provide a grade A atmosphere as defined by the Rules and Guidance for Pharmaceutical Manufacturers and Distributors (Medicines and Healthcare products Regulatory Agency, 2017). However, it is becoming increasingly common for testing to be undertaken in an isolator that physically separates the operator from the test materials and so reduces the incidence of false-positive test results due to extraneous contamination introduced during the test itself. Such isolators are similar in principle to a glove box, and typically consist of a cabinet (supported on legs or a frame) that is sufficiently large for the operator, who is covered by a transparent hood of moulded flexible plastic forming the cabinet base, to sit or stand within it. The direct inoculation method involves the removal of samples from the product under test and their transfer to a range of culture media that might be expected to support the growth of contaminating organisms. After incubation, the media are examined for evidence of growth, which, if present, is taken to indicate that the product may not be sterile. It is not certain that the product is contaminated because the organisms responsible for the growth may have arisen from the operator or may have already been present in the media to which the samples were transferred, i. Thus, in conducting a sterility test it is necessary to include controls that indicate the likelihood of the contaminants arising from these sources; these are discussed hereafter. The size and number of the samples to be taken are described in the PhEur (European Pharmacopoeia Commission, 2017). It is necessary to inactivate any antimicrobial substances contained in the sample. This alternative method of conducting sterility tests is obviously only applicable to aqueous or oily solutions that will pass through a membrane having a pore size sufficiently small to retain bacteria. The membrane, and hence the bacteria retained on it, is washed with isotonic salts solution, which should remove any last traces of antimicrobial substances. This method is certainly to be preferred to direct inoculation because there is a greater chance of effective neutralization of antimicrobial substances. This is almost invariably water because most other common solvents have antimicrobial activity. If no suitable solvent can be found, the broth dilution method is the only one available. If there is no specific inactivator available for antimicrobial substances that may be present in the solid, then their dilution to an ineffective concentration by use of a large volume of medium is the only course remaining. The controls associated with a sterility test are particularly important because incomplete control of the test may lead to erroneous results. Failure to neutralize a preservative completely may lead to contaminants in the batch going undetected and subsequently initiating an infection when the product is introduced into the body. The PhEur (European Pharmacopoeia Commission, 2017) recommends that four controls are incorporated. The so-called growth promotion test simply involves the addition of inocula with low counts (not more than 100 cells or spores per container) of suitable test organisms to the media used in the test to show that they do support the growth of the common contaminants for which they are intended. Organisms having particular nutritional requirements, such as blood, milk or serum, are not included, so they, in addition to the more obvious omissions such as viruses, cannot be detected in a routine sterility test because suitable culture conditions are not provided. On the other hand, it is impossible to design an all-purpose medium, and sterilization processes that kill the spore-forming bacteria and other common contaminants are likely also to eradicate the more fastidious pathogens such as streptococci and Haemophilus species, which would be more readily detected on blood-containing media. This argument does not, however, cover the possibility of such pathogens entering the product, perhaps via defective seals or packaging, after the sterilization process itself and then going undetected in the sterility test. The second control, termed the method suitability test, is intended to demonstrate that any preservative or antimicrobial substance has been effectively neutralized. This requires the addition of test organisms to containers of the various media as before but, in addition, samples of the material under test must also be added to give the same concentrations as those arising in the test itself. For the sterility test as a whole to be valid, growth must occur in each of the containers in these controls. It is necessary also to incubate several tubes of the various media just as they are received by the operator. If the tubes are not opened but show signs of growth after incubation, this is a clear indication that the medium is itself contaminated. This should be an extremely rare occurrence but, in view of the small additional cost or effort, the inclusion of such a control is worthwhile. A control to check the likelihood of contamination being introduced during the test should be included in the programme of regular monitoring of test facilities. These items, identical to the sample to be tested, are manipulated in exactly the same way as the test samples. If, after incubation, there are signs of microbial growth in the media containing these negative controls, the conclusion is drawn that the contamination arose during the testing process itself. Some items present particular difficulties in sterility testing because of their shape or size. These problems are most conveniently overcome simply by testing the whole sample rather than attempting to withdraw a portion of it.

It is no good antibiotic eye drops order nitrofurantoin overnight delivery, for example infection game tips buy cheap nitrofurantoin 100 mg, to define the level of the flocculation modifier to give perfect flocculation behaviour and then add a buffer to the system antibiotics for dogs at feed store order nitrofurantoin with mastercard, which will release mobile ions into the diffuse layer and change the flocculation status antibiotics on the pill buy cheap nitrofurantoin 100 mg. Flocculation modifiers are ionic materials which ionize once in solution in the suspension medium pcr antibiotic resistance buy 100 mg nitrofurantoin amex. The effect of the flocculation modifier on the flocculation behaviour of the particles is dependent on the ionic strength in solution, and therefore a multivalent salt. Colloid stabilizers A colloid stabilizer is a material which will prevent or retard the coalescence of particles suspended in a medium and, as such, will encompass any material acting on the particle surface or in the diffuse layer. However, the term is usually understood to mean surfactants which are deposited on the particle surface, which were discussed earlier. Flocculation modifiers In previous sections, the necessity of understanding particulate behaviour in suspension was stressed. Materials which deposit onto the surface of the particle, such as surfactants, will affect the surface potential, o, leading to a secondary effect on the thickness of the diffuse layer by changing the Stern potential. Materials which ionize in solution, such as preservatives and buffers, will lead to mobile charges being taken into the diffuse layer, resulting in a thinning of the diffuse layer and, generally, increased flocculation behaviour. Excipients are added to pharmaceutical suspension formulations for various good scientific reasons, such as buffering, antimicrobial preservation and viscosity modification, as discussed earlier. However, their combined effects on the particulate behaviour must be understood and quantified. The last excipient to be added to the suspension formulation is the flocculation modifier, its function being to adjust the flocculation status of the particles to that which is intended. The quantity of flocculation modifier required must be determined last, once the levels 444 Stability considerations for suspensions General chemical stability considerations apply to suspensions as much as to any other formulation. If the chemical degradation pathway of the drug is determined, then the appropriate chemical preservative(s) can be added to the suspension. Similarly, the effect of temperature on the chemical stability of the drug needs to be established, to assess whether any temperature restrictions are necessary during storage or transport. Sedimentation should ideally be kept to a minimum, as discussed previously, and where sedimentation is permitted or unavoidable, easy redispersion of the sediment is necessary. The patient or carer should be able to redisperse the sediment by inversion and gentle shaking of the bottle only; the bottle should carry an appropriate instruction. Visual assessment of sediment redispersion on shaking is useful but can provide only a general indication of whether there is a problem or not. A more quantitative approach involves assessment of the particle size distribution and drug content of representative samples taken from the top, middle and bottom of the container. Ideally, these should be consistent across depth and over time, meeting the preset product specifications. Packaging of the suspension into containers will require a stirred hopper to minimize settling during the packaging process, and the effect of shear at the dispensing nozzle on the suspension will need to be considered. The drug is usually the most expensive item in the formulation, particularly for an investigative drug not yet licensed, and this will be no different for suspensions. Manufacturing considerations Suspensions are more challenging to prepare than solution formulations. On both a dispensary scale and a factory scale, the most important part of the process is the initial dispersion stage, whereby the powdered drug is mixed with the carrier vehicle. They require large quantities of pharmaceutical-grade Summary Suspensions are one of the most challenging pharmaceutical formulations that students and formulators are likely to meet. Successful suspension development is dependent on a basic understanding of the interactions between particles in the suspension and between particles and other formulation ingredients. Emulsions, Foams, Suspensions and Aerosols: Microscience and Applications, second ed. Multiple emulsions can also be formed from oil and water by the reemulsification of an existing emulsion to form two dispersed phases. For example, multiple emulsions can be described as oil-in-water-in-oil (o/w/o) emulsions. The increase in surface free energy G brought about by the formation of droplets and the corresponding increase in surface area A is given in Eq. In order to reduce this surface free energy, the droplets assume a spherical shape; this gives a minimum surface area per unit volume. On contact, droplets will coalesce (merge and recombine) in an attempt to reduce the total interfacial area (and thus the total surface energy, as indicated by Eqn 27. Thus emulsification can be considered to be the result of two competing processes that occur simultaneously. The first process requires energy input to disrupt the bulk liquids and form fine droplets, thereby increasing the free energy of the system. The second process, which involves the coalescence of droplets, occurs spontaneously to reduce the interfacial area and minimize the free energy. If agitation ceases altogether, coalescence will continue until complete phase separation is obtained, the state of minimum free energy. Droplet diameters vary enormously in pharmaceutical emulsions, but typically cover the range 0. The visual appearance of an emulsion reflects the influence of droplet size on 448 light scattering, and ranges from transparent or translucent for emulsions composed of small nanosized droplets (smaller than ~200 nm) to milky white and opaque for emulsions containing larger droplets. Partially miscible liquids When oil and water phases are partially miscible, droplet growth with eventual phase separation may occur by Ostwald ripening rather than coalescence. Ostwald ripening does not require any contact between droplets and is an important mechanism of instability in sub-micrometre pharmaceutical emulsions. Emulsions in pharmacy Emulsions can be formulated for virtually all the major routes of administration, although most commercial products are developed for the oral, parenteral and topical routes. Oral and intravenous emulsions are almost exclusively of the o/w type, whereas dermatological emulsions, and emulsions for subcutaneous or intramuscular injection may also be formulated as w/o emulsions. The unpleasant taste of the oil is masked by the aqueous phase and any odour is suppressed when it is administered as the internal phase of an o/w emulsion. O/w emulsions containing vegetable oils are also used for the oral delivery of drugs and vitamins of low aqueous solubility. Intestinal absorption is generally enhanced when an oily solution of a drug is presented in the form of small sub-micrometre oil droplets, because of the larger interfacial area available for contact at the absorption site. Absorption is also generally faster and more complete than from suspension or tablet forms, because the drug in oral emulsions is already solubilized in the oil, thus eliminating the dissolution step prior to absorption. Oral drug delivery using emulsions can be unpredictable because emulsions may become unstable in the low-pH environment of the stomach. Emulsion concentrates, described as self-emulsifying drug delivery systems, are available commercially to minimize instability. They are not themselves emulsions, but form an emulsion on mild agitation in the aqueous environment of the stomach. Sterile intravenous lipid o/w emulsions are used clinically as a source of calories and essential fatty acids for debilitated patients. Intralipid) are also used as intravenous drug carriers for drugs of limited water solubility; marketed products are available for drugs such as diazepam (Diamuls), propofol (Diprovan) and vitamin K (Phytonadione). The advantages of such intravenous emulsions over solution formulations (in which the drug is solubilized by various cosolvents, and/or surfactants and/or pH control) include a higher drug payload, lower toxicity, less pain on injection and protection of labile drugs by the oily environment. Emulsions incorporating contrast agents (iodized oils, bromized perfluorocarbon oils) are used in diagnostic imaging, including X-ray examinations of body organs, computed tomography and magnetic resonance imaging. W/o emulsions administered by the subcutaneous or intramuscular routes can be used to prolong the delivery of water-soluble antigens and thus provide a longer-lasting immunity. The antigen or drug must first diffuse from the aqueous droplets through the oily external phase before it reaches the tissues. Such emulsions are sometimes difficult to inject because of the high viscosity of the oily continuous phase. Multiple w/o/w emulsions, which are less viscous, have also been investigated for the prolonged release of drugs and vaccines incorporated in the innermost aqueous phase (see Chapter 36). Dermatological emulsions are the largest class of emulsions used in pharmacy, and range in consistency from structured fluids (lotions, liniments) to semisolids (creams). Both o/w and w/o emulsions are extensively used as vehicles to deliver drugs to the skin, and for their therapeutic properties. W/o emulsions tend to be greasy, and although this conveys a greater feeling of richness, w/o emulsions do not mix well with aqueous wound exudates and are also sometimes difficult to wash off the skin. They do, however, hydrate the skin by occlusion, an important factor in drug permeation. In contrast, o/w lotions and creams readily mix with tissue exudates and are more easily removed by washing. Dermatological emulsions (see Chapter 40) facilitate drug permeation into and through the skin by occlusion, by the incorporation of penetration-enhancing components and/or by evaporation on the skin surface. As most o/w creams are applied and rubbed onto the skin as a thin film, the drug delivery system is not the bulk emulsion but rather a dynamic evaporating film in which the dissolution environment and partitioning environment alter as the relative concentrations of the volatile ingredients change. Rapid evaporation may temporarily supersaturate the film, increasing thermodynamic activity and drug permeation. Whilst dermatological emulsions and creams are two-phase systems, single-phase systems, including ointments and gels, are also available for topical application. Development of pharmaceutical emulsions Although emulsions have many distinct advantages over other dosage forms, often increasing bioavailability and reducing side effects, there are relatively few commercial oral or parenteral emulsions available. This comparative lack of use is due to the fundamental problems of maintaining emulsion stability. However, there is currently a large increase in research into all aspects of emulsions, although as yet there are few new products. This resurgence of interest, which is mainly focused on lipid emulsions for local or intravenous delivery, combines nanoscience with the drive for cell-selective drug targeting and delivery. Nanoemulsions Nomenclature relating to nanoemulsions It is necessary to spend a little time here considering the nomenclature of nanoemulsions as unfortunately there is some confusion in the literature, and definitions may vary. Although both microemulsions and nanoemulsions are clear and transparent, they are structurally quite different. Nanoemulsions are thermodynamically unstable dispersions of oil and water that contain individual small droplets less than 200 nm in diameter. They are thermodynamically stable, single-phase systems that form spontaneously and have a number of different microstructures depending on the nature and concentration of the components (see also Chapter 5). According to the convention for emulsions and their small droplet sizes enable them to penetrate deep into the tissues through fine capillaries. Thus such emulsions are being investigated extensively as drug carriers and for their ability to target specific sites in the body, including the liver and the brain. The surface properties of emulsions can be modified by control of the charged nature of the interfacial film or by incorporation of homing devices into the film to target specific tissues and organs after injection. Negatively charged droplets are cleared more rapidly from the blood than neutral or positively charged ones. Positively charged (cationic) nanoemulsions have also been shown to increase skin permeation of poorly soluble antifungal drugs and ceramides due to their interaction with the negatively charged skin epithelia cells. W/o nanoemulsion formulations are under investigation in cancer chemotherapy for prolongation of drug release after intramuscular or intratumoral injection, and as a means of enhancing the transport of anticancer agents via the lymphatic system. Emulsion theory related to pharmaceutical emulsions and creams the classical theories of emulsification for simple two-phase oil and water model emulsions based on droplet interactions and interfacial films are considered in Chapter 5. However, commercial pharmaceutical emulsions (even dilute mobile fluids for intravenous administration) are rarely such simple oil and water systems. A unified theory of emulsification cannot be applied quantitatively to such multiphase emulsions, which range in consistency from mobile or structured fluids to soft or stiff semisolids. Formulation of emulsions When a formulator is formulating a pharmaceutical emulsion, the choice of oil, emulsifier and emulsion type (o/w, w/o or multiple emulsion) will depend on the route of administration and its ultimate clinical use. The potential toxicity of all the excipients, their cost and possible chemical incompatibilities in the final formulation must also be identified. It is sometimes difficult to isolate these effects in practical emulsions as each is dependent on, and influenced by, the other. Thus ingredient selection is made often by trial and error and is dependent on the experience of the formulator. Selection of the oil phase the oil used in the preparation of pharmaceutical emulsions may be the medicament itself or it may function as a carrier for a lipid-soluble drug. The selection of the oil phase will depend on many factors, including the desired physical properties of the emulsion, the miscibility of the oil and aqueous phases, the solubility of the drug (if present) in the oil and the desired consistency of the final emulsion. Some oils, in particular unsaturated oils of vegetable origin, are liable to undergo auto-oxidation and become rancid, and so antioxidants or preservatives must be incorporated into the emulsion to inhibit this degradation process. Liquid paraffin, either alone or combined with soft or hard paraffin, is used in numerous dermatological lotions and creams, both as a vehicle for the drug, and for the occlusive and sensory characteristics imparted when the emulsion is spread onto the skin. Turpentine oil, benzyl benzoate and various silicone oils are examples of other externally applied oils that are formulated as emulsions. In oral emulsions, the most widely used medicinal oils are castor oil and liquid paraffin, which are nonbiodegradable and provide a local laxative effect in the gastrointestinal tract, fish liver oils. Vegetable oils are also used as drug carriers as they are readily absorbed in the gastrointestinal tract. The oil phase is rarely inert, as it may have an impact on bioavailability by its influence on gastric emptying time. The choice of oil is severely limited in emulsions for parenteral administration, as many are inherently toxic. Although purified mineral oil is used in some w/o depot preparations for intramuscular injection, where its potential toxicity. A range of purified vegetable oils have been used, almost exclusively over many years in lipid emulsions for parenteral nutrition and as intravenous carriers for drugs of limited aqueous solubility. Although a large number of vegetable oils have been investigated as possible stable, nontoxic oils for use in lipid emulsions, most commercial products contain soya bean or safflower oils because of their high content of the essential fatty acid linoleic acid. These provide a more rapidly available source of energy, as well as enhancing the solubilizing capacity for lipid-soluble drugs, including ciclosporin.

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Sugars in low concentration provide an energy source for microbial contamination (at much higher concentrations antibiotic resistance vaccines buy nitrofurantoin cheap, sugar solutions are hypertonic infection 3 months after abortion nitrofurantoin 50 mg buy with visa, leading to lysis of bacterial cells antibiotics without penicillin purchase 100 mg nitrofurantoin fast delivery, and so are self-preserving) what kind of antibiotics work for sinus infection cheap nitrofurantoin 100 mg free shipping, so adequate antimicrobial preservation would be required antibiotics for acne alternatives purchase line nitrofurantoin. Additionally, most medicines are formulated, if at all possible, as sugar-free products, so this would not necessarily be a recommended formulation strategy. Viscosity modifiers are also known as suspending agents as they will reduce the sedimentation of the particles and keep them suspended for longer. The viscosity of the system can be easily adjusted by the addition of polymeric materials or inorganic materials such as clays. The target viscosity for each preparation needs to be defined so as to maintain the particles in their suspended state for as long as possible, i. However, this must be balanced against the ease of use of the product; whilst a very viscous suspension will show little, if any, sedimentation, it is unlikely to be patientfriendly. The product must be pourable from a bottle onto a spoon for oral use or dispensable through a nozzle if it is intended for ocular or nasal use. Cellulosic materials are commonly used as viscosity enhancers in suspension formulations. Cellulose itself is a linear polymer of D-glucose, with individual glucose units being linked via (14) glycosidic bonds; the number of repeating units may run into Buffers A buffer is defined as a mixture of a weak acid or base and one of its salts and is designed to maintain the pH of an aqueous system within very narrow limits. Buffers may be used in suspension formulations if a particular pH is required because of the route of administration, or if the solubility of the drug is suppressed by it being formulated at a particular pH, as discussed earlier. Because of its ionic nature, a buffer system will contribute charges to the formulation, which will affect the flocculation behaviour of the suspension by virtue of their being associated with the diffuse layer surrounding the particle. The use of a buffer may also affect the ionization state of other components, such as preservatives, with subsequent effects on their efficacy and the concentration required. Cellulose ethers are more often used, and these are obtained from native cellulose by chemical treatment with an appropriate reagent, replacing the hydrogen on the hydroxyl group of the glucose residue with an appropriate alkyl, hydroxyalkyl or carboxyalkyl group. There are three hydroxyl groups on each glucose residue in the cellulose chain, and the extent of conversion is measured by the degree of substitution. All five cellulosic polymers mentioned (methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose) are water soluble and are available in a range of molecular weights and degrees of substitution, which leads to a range of solution viscosities being easily obtainable by manipulation of the chemical properties and concentrations of the polymers used. Generally speaking, the polymers will not interfere with the flocculation behaviour of the particles. However, the ionic nature of sodium carboxymethylcellulose will directly lead to the production of Na+ ions in solution, which will migrate into the diffuse layer around the particles and affect their flocculation behaviour, so care should be taken with this excipient. Alginic acid, a polymer derived from seaweed, can also be used to enhance the viscosity of the medium and reduce sedimentation. It comprises residues of -d-mannuronic acid and -l-guluronic acid joined via a (14) link; macroscopically, the polymer consists of linear blocks of one or other of the two individual components, with a third type of block showing an alternating structure of the two residue types. This structural variety is a consequence of its natural origin, different sources producing alginic acid with different blocking arrangements, and gives rise to differing properties in solution. Alginic acid is easily ionized and is commonly used as the sodium salt, so in this case it will have a direct effect on flocculation behaviour. In terms of suspension formulation, therefore, addition of alginic acid, either as the intact acid or as the sodium salt, will extract Ca2+ ions from the surroundings if they are present in the formulation. The effects of this will be both to change the flocculation behaviour of the particles and to increase the viscosity of the system. Traditionally, clays and gums were used to thicken suspensions and to retard sedimentation. Clays are water-insoluble inorganic materials that, when dispersed in water, will absorb water into their structure rather than dissolve. A clay suspension shows some rheological structuring and will retard the sedimentation of other materials suspended with it, such as the drug in pharmaceutical suspensions. Ultimately, the clay will itself sediment as it is in suspension rather than in solution, as are the polymers already discussed. Once dissolved in water, gum arabic forms a reasonably viscous solution which can be used to retard sedimentation of suspended materials. Depending on the source, for example precisely which species of Acacia, the chemical composition will be different and hence the suspending capabilities will be variable. Tragacanth, sometimes known as gum tragacanth, is another complex polysaccharide mixture, derived from the sap of plants of the genus Astragalus. As with gum arabic, it is used to increase the viscosity of the suspending medium and to retard sedimentation of the drug particles. Clays and gums are natural materials and are subject to much greater batch-to-batch variation than synthetic or semisynthetic materials, and so have fallen out of favour as pharmaceutical excipients, where close control and predictability of physical and/or chemical behaviour is a prerequisite. Wetting agents Wetting agents are used to improve the flow of the liquid vehicle across the particle surface, which in turn increases the homogeneity of distribution of the drug particles throughout the formulation. Above the cmc, micelles are formed with a hydrophobic core, and the hydrophobic drug will begin to dissolve into this region, thus affecting the structure of the system. Surfactants will localize on the surface of the particle, affecting the surface charge, o. The overall effect will be determined by the chemical nature of the surfactant and may be an increase or a decrease in the magnitude of the charge, but keeping the same sign. Each of these changes will have a direct effect on the Stern potential, and an indirect effect on the thickness of the diffuse layer, resulting in alteration of the flocculation behaviour of the system. Additionally, ionic surfactants such as sodium lauryl sulfate will release mobile ions when dissolved and will have a separate effect on the diffuse layer. Mixtures containing both long-chain and mediumchain triglycerides have been adopted in some commercial preparations (Table 27. Emulsified perfluorochemicals are also considered acceptable for intravenous use provided that they are excreted relatively quickly. A major problem in the formulation of the early perfluorocarbon emulsions as blood substitutes was that the oils that formed the most stable emulsions were not cleared rapidly from the body. Selection of the emulsifying agent (emulsifier) Emulsifiers are used to control emulsion stability during a shelf life that can vary from days for extemporaneously prepared emulsions to months or years for commercial preparations. In practice, combinations of emulsifiers rather than single agents are generally used. The choice of emulsifier depends on the type of emulsion to be prepared, emulsifier toxicity (or irritancy if applied to the skin) and potential cost and availability. The final clinical use of the emulsion is also an important consideration, as emulsifiers control the in vivo fate of emulsions by their influence on droplet size distribution, and the charge and surface properties of the individual droplets. An ideal preservative should exhibit a wide spectrum of activity against bacteria and fungi; it should also be free from toxic, irritant or sensitizing activity (see Chapter 48). Large-volume injectable fat emulsions do not contain preservatives, and sterilization is achieved by autoclaving without a preservative. Phenoxyethanol, benzoic acid, and the p-hydroxybenzoates are used as preservatives in oral and topical emulsions. The preservative will partition between the oil and aqueous phases, with the oil phase acting as a reservoir. Aqueous pH is an additional factor to be considered, as a sufficient concentration of the un-ionized form must be present to ensure proper preservation. Antioxidants and humectants Antioxidants are added to some emulsions to prevent oxidative deterioration of the oil, emulsifier or the drug itself during storage. The antioxidants commonly used in pharmacy include butylated hydroxyanisole and butylated hydroxytoluene at concentrations up to 0. Humectants, such as propylene glycol, glycerol and sorbitol at concentrations up to 5%, are often added to dermatological preparations to reduce the evaporation of the water from the emulsion during storage and use. However, high concentrations may also remove moisture from the skin, causing dryness. Other excipients Preservatives the aqueous continuous phase of an o/w emulsion can produce ideal conditions for the growth of bacteria and fungi. The potential sources of contamination may be from the water used, from the raw materials (especially if these are natural products), from the manufacturing and packaging equipment or introduced by the patient during use. Such contamination, which may constitute a health hazard, can also affect the physicochemical properties of the formulation, causing colour, odour or pH changes and even phase separation. W/o emulsions are less susceptible to such contamination because the aqueous phase is essentially enclosed and protected by the oil. The dispersed droplets do not retain their initial character because the emulsion becomes thermodynamically stable (for the free energy is still high) but rather because the added emulsifiers inhibit or delay the processes of coalescence and Ostwald ripening (described later). Emulsifiers generally impart time-dependent stability by the formation of a mechanical or electrostatic barrier at the droplet interface (an interfacial film) or in the external phase (a rheological barrier). The formation of interfacial films by adsorption of the emulsifier at the oil­water interface is discussed in Chapter 5. The interfacial film may increase droplet­droplet repulsion by the introduction of electrostatic or steric repulsive forces to counteract the van der Waals forces of attraction. Electrostatic repulsions are important in o/w emulsions stabilized by ionic emulsifiers, whereas steric repulsive forces, which arise when hydrated polymer chains approach one another, dominate with nonionic emulsifiers and in w/o emulsions. The interfacial film may also provide a mechanical barrier to prevent droplet coalescence, particularly if it is close packed and elastic. Although this facilitates the formation of droplets during emulsification and reduces the thermodynamic tendency for coalescence, interfacial tension reduction is not a major factor in maintaining long-term stability. Interfacial films do not have the dominant role in maintaining stability in many practical emulsions in which the external phase is thickened by the emulsifier, i. In these, the structured continuous phase forms a rheological barrier which prevents the movement and hence the close approach of droplets. Emulsifiers that thicken the external phase but do not form an interfacial film are variously described as auxiliary emulsifiers, coemulsifiers or viscosity enhancers. Many pharmaceutically important mixed emulsifiers, including lecithin and the emulsifying waxes, form interfacial films at low concentration and also structure the external phase at higher concentrations by the formation of additional lamellar liquid crystalline phases (with lecithins) or crystalline gel network phases (with emulsifying waxes). Emulsion type the type of emulsion that forms (whether o/w or w/o or multiple emulsion) and the droplet size distribution depend on a number of interrelated factors, including the method of preparation (energy input), the relative volumes of the oil and water phases and the chemical nature of the emulsifying agent. When oil and water are mixed vigorously in the absence of an emulsifier, droplets of both liquids are produced initially, with the more rapidly coalescing droplets forming the continuous phase. Generally this is the liquid present in the greater amount because the greater number of droplets formed increases the probability of droplet collision and subsequent coalescence. With the inclusion of an emulsifier, the type of emulsion that forms is no longer a function of phase volume alone, but also depends on the relative solubility of the emulsifier in the oil and water phases. In general, the phase in which the emulsifying agent is more soluble (or in the case of solids, more easily wetted by) will form the continuous phase. Theoretically, the dispersed phase of an emulsion can occupy up to a maximum of 74% of the phase volume. Whilst such high internal phase o/w emulsions stabilized by suitable emulsifiers have been produced, it is more difficult to form w/o emulsions with greater than 50% dispersed phase because of the steric mechanisms involved in their stabilization. Classification of emulsifying agents Emulsifying agents may be classified into two groups: (1) synthetic or semisynthetic surface-active agents and polymers and (2) naturally occurring materials and their derivatives. Surface-active agents and polymers Surface-active agents (surfactants for short) are further classified as ionic. Their emulsifying power is influenced by batch variations in the homologue composition, with pure homologue surfactants proving to be very poor emulsifiers. In general, cationic surfactants are the most toxic and irritant and nonionic surfactants the least. Thus, for pharmaceutical emulsions, ionic synthetic surfactants are used only in external topical preparations, where they are present at relatively low concentration. Both ionic and nonionic surfactants are combined with fatty alcohols to produce anionic, cationic or nonionic emulsifying waxes, which are used to both stabilize and structure aqueous lotions and creams. The nonionic block copolymer poloxomer 188 (Pluronic F68) has been used in perfluorochemical emulsions for intravenous infusion, although some patients are sensitive to this emulsifier. For example, in white liniment, ammonium oleate is formed in situ from the reaction between ammonia solution and oleic acid. Calcium salts of fatty acids containing two hydrocarbon chains form w/o emulsions because of their limited solubility in water. These are generally formed in situ by the interaction of calcium hydroxide with a fatty acid. In zinc cream, calcium oleate is formed in situ from the interaction between oleic acid and calcium hydroxide. This approach is also used in some formulations of oily calamine cream, in which oleic acid and some of the free fatty acid component of arachis oil are partially neutralized by calcium hydroxide to form a calcium oleate­oleic acid mixed emulsifier. Anionic surfactants Anionic surfactants dissociate at high pH to form a long-chain anion with surface activity. Emulsifying properties are lost and emulsions are unstable in acid conditions and in the presence of cationic materials, such as cationic surfactants and polymers. Examples of anionic surfactants are described in the following paragraphs: Cationic surfactants Cationic surfactants dissociate at low pH to form a long-chain surface-active cation. Emulsions containing cationic surfactant as the emulsifier are unstable at high pH and in the presence of anionic materials, including anionic surfactants and polymers. Sodium lauryl sulfate (sodium dodecyl sulfate) was until recently the most widely used surfactant in topical products. The commercial sulfate is actually a mixture containing predominantly the C12 homologue, but also contains some C14 and C16 homologues. Sodium lauryl sulfate alone is a weak emulsifier of the o/w type, but forms a powerful o/w blend when it is used in conjunction with cetostearyl alcohol. Emulsifiers in this group consist mainly of the alkali salts of long-chain fatty acids. These constitute an important group of cationic emulsifiers in dermatological preparations because they also have antimicrobial properties. Cetrimide (cetyltrimethylammonium bromide) is blended with cetostearyl alcohol to form cationic emulsifying wax, which is the mixed emulsifier used in cetrimide cream. Nonionic surfactants There are an enormous number of nonionic surfactants available commercially with different oil and water solubility producing either o/w emulsions or w/o emulsions. Nonionic surfactants are particularly useful as emulsifiers because they are less toxic and irritant than ionic surfactants, and therefore a limited number.

This includes the provision of air for equipment such as fluidized-bed processors (see Chapters 28 and 29) bacteria klebsiella pneumoniae cheap nitrofurantoin 50 mg with visa, film-coating machinery (see Chapter 32) and bottle-cleaning equipment so that product appearance and quality are maintained virus removal tool kaspersky discount 50 mg nitrofurantoin. The use of suitable filters also enables the particulate contamination of air in manufacturing areas to be maintained at an appropriate level for the product being manufactured; for example virus on mac computers buy genuine nitrofurantoin online, air free from microorganisms can be supplied to areas where sterile products are being manufactured antibiotics for acne alternatives nitrofurantoin 50 mg purchase free shipping. This filter is used for solid­liquid filtration processes infection sepsis purchase genuine nitrofurantoin on line, but the same basic principles are valid whatever filtration process is being evaluated. Suspended solids may, however, have sufficient momentum such that they do not follow the fluid path but impinge on the filter fibre and are retained, owing to attractive forces between the particle and the fibre. Where the pores between filter fibres are larger than the material being removed, some particles may follow the fluid streamlines and miss the fibre, this being more likely if the particles are small (owing to their lower momentum) and as the distance from the centre of the fibre towards which they approach increases. To ensure the removal of all unwanted material, filter media that use the impingement mechanism must be sufficiently thick so that material not trapped by the first fibre in its path is removed by a subsequent one. The fluid should flow through the filter medium in a streamlined manner to ensure the filter works effectively, as turbulent flow may carry the particles past the fibres. Depth filters are the main type of filter used for removal of material from gases. It is the Attractive forces Electrostatic and other surface forces may exert sufficient hold on the particles to attract and retain them on the filter medium (as occurs during the impingement mechanism). Air can be freed from dust particles in an electrostatic precipitator by passing the air between highly charged surfaces, which attract the dust particles. Büchner flask Autofiltration Autofiltration is the term used to describe the situation when filtered material (termed the filter cake) acts as its own filter medium. The difference between atmospheric pressure and the lower pressure in the flask is added to the pressure due to the unfiltered product to give the total pressure difference. A viscous fluid will filter more slowly than a mobile one owing to the greater resistance to movement offered by more viscous fluids (see Chapter 6). The cake will increase in thickness as filtration proceeds, so if it is not removed, the rate of filtration will fall. The total volume of filtrate flowing through the filter will be directly proportional to the area of the filter, and hence the rate of filtration can be increased by using either larger filters or a number of small units in parallel. Both of these approaches will also distribute the cake over a larger area and thus decrease the value of L, thereby further increasing the filtration rate. The contribution to resistance to filtration from the filter medium is usually small compared with that of the filter cake, and can often be disregarded in calculations. The proportionality constant K (m2) expresses the permeability of the filter medium and cake and will increase as the porosity of the bed increases. It is clearly desirable that K should be large so as to maximize the filtration rate. If K is taken to represent the permeability of the cake, it can be shown that K is given by K= e2 5(1 - e)2 S2 (25. If the solid material is one that forms an impermeable cake, the filtration rate may be increased by adding a filter aid (discussed later), which aids the formation of open porous cakes. Often this driving force is too low for an acceptably fast filtration rate and there is a requirement to increase it. In practice, however, it will be less, as liquids will boil in the collecting vessel if the pressure is reduced to too low a value. Despite the limited pressure difference generated, vacuum filtration is used in the laboratory, where there are safety advantages in using glassware, because if the glassware is damaged, it will implode rather than explode. One important industrial filter, the rotary vacuum filter, also uses a vacuum; this is described later in this chapter. With industrial-scale liquid filtration, commonly used means of obtaining a high-pressure difference are either pumping the material to be filtered into the filter with a suitable pump or using a pressurized vessel to drive the liquid through the filter. Most industrial filters have a positive-pressure feed; the pressure used is limited only by the pump capacity and the ability of the filter to withstand the highpressure stress. Although increasing the P value in the absence of any other changes will cause a proportional increase in the filtration rate, care needs to be taken to ensure that a phenomenon known as cake compression does not occur. Too high an applied pressure may cause the particles making up the cake to deform and therefore decrease the voidage (bed porosity). The effect of decreasing K greatly outweighs any increase in the filtration rate arising from a thinner cake. This is most likely in the early stages before a continuous layer of cake has formed. As a general rule, filtration should start at moderate pressure, which can be increased as filtration proceeds and the cake thickness builds up. To increase the filtration rate, the viscosity of the filtrate can be reduced in most cases by heating of the formulation to be filtered. Care needs to be taken with this approach when one is filtering formulations containing volatile components, or if the components are thermolabile. In such cases, dilution of the formulation with water may be an alternative means of reducing the viscosity providing that the increase in the filtration rate exceeds the effect of increasing the total volume to be filtered. Filter aids that are used include diatomite (a form of diatomaceous earth) and perlite (a type of naturally occurring volcanic glass), which has been used in the filtration of, for example, penicillin and streptomycin. The use of filter aids is obviously not appropriate if the filtered material is the intended end product. Filtration equipment the filtration equipment described in this chapter is that used for filtering liquids. The flow through Equipment selection Ideally the equipment chosen should allow a fast filtration rate to minimize production costs, be cheap to buy and use, be easily cleaned and resistant to corrosion, and be capable of filtering large volumes of product before the filter needs to be stripped down for cleaning or replacement. There are a number of product-related factors that should be considered when one is selecting a filter for a particular process. This effect is commonly observed when one is filtering formulations in the laboratory using filter paper in a funnel. In some cases, if the cake is allowed to build up, the process slows to an unacceptable rate, or may almost stop. In these situations, it may be necessary to remove the cake periodically or to maintain it at a constant thickness, as occurs, for example, with the rotary drum filter. As previously mentioned, the cake thickness can be kept lower by using a larger filter area. In addition, it may reduce the compressibility of the cake and/or prevent the Interactions with the filter medium may lead to leaching of the filter components, degradation or swelling of the filter medium or adsorption of components of the filtered product onto the filter. All of these may influence the efficiency of the filtration process or the quality of the filtered product. These dictate the size and type of equipment and the amount of time needed for the filtration process. High operating pressures require that the equipment is of sufficient strength and that appropriate safe operating procedures are adopted. This will dictate the pore size of membrane filters or the filter grade to be used. If sterility is required, the equipment should itself be capable of being sterilized and care must be taken to ensure that contamination does not occur after the product has passed the filter. The incoming formulation can be heated, or steam-heated jackets can be fitted to the equipment. Care should be taken to ensure the equipment seals, for example, can operate at elevated temperatures. Industrial filtration equipment Filters for liquid products may be classified by the method used to drive the filtrate through the filter medium. Filters can be organized into three classes: namely, gravity, vacuum and pressure filters. Gravity filters are, however, simple and cheap, and are frequently used in laboratory filtration, where volumes are small and a low filtration rate is relatively unimportant. Vacuum filters the rotary vacuum filter In large-scale filtration, continuous operation is often desirable, and this may be difficult to achieve when it is necessary to filter slurries containing a high proportion of solids. The rotary vacuum filter is continuous in operation and has a system for removing the cake so that it can be run for long periods handling concentrated slurries. It can be visualized as two concentric cylinders with the annular space between them divided into a number of septa by radial partitions. Each septum has a radial connection to a complicated rotating valve whose function is to perform the sequence of operations listed in Table 25. The cylinder rotates slowly in the slurry, which is kept agitated, and a vacuum applied to the segments 422 In some cases, for example when the solid is the required product, the same receiver may be used for the filtrate and for wash water. When the deposited cake leaves the slurry bath, the vacuum is maintained to draw air through the cake, thus aiding liquid removal. The cake is removed by the scraper blade aided by compressed air forced into the septa. It is the function of the rotary valve to direct these services into each septum when required. Cake compression rollers are often fitted to improve the efficiency of washing and draining if the cake on the drum becomes cracked. During the actual filtration, the scraper knife is set to move slowly inwards, removing the blocked outer layer of the filter aid and exposing fresh surface. If removal of the cake presents problems, a string discharge filter may be employed. This is useful for filtration of the fermentation liquor in the manufacture of antibiotics, when a felt-like cake of mould mycelia must be removed. The cake is broken by the sharp bend over the rollers and collected, and the bands return to the drum. The advantages of the industrial rotary vacuum filter can be summarized as follows: · It is automatic and continuous in operation, so labour costs are low. On the other hand, if the solids are coarse and form a porous cake, the thickness may be 100 mm or more. The disadvantages of the rotary vacuum filter include the following: Small rotary vacuum filter units with a drum approximately 120 mm long and 75 mm in diameter are also available. These are simpler in construction than the larger industrial-type units as they do not have a cake-washing facility. They have disposable filter drums and can filter batches from approximately 100 L to 700 L at a rate of 1 L min-1 to 2 L min-1. The rotary filter is most suitable for continuous operation on large quantities of slurry, especially if the slurry contains considerable amounts of solids. Examples of pharmaceutical applications include the collection of calcium carbonate, magnesium carbonate and starch, and the separation of the mycelia from the fermentation liquor in the manufacture of antibiotics. Pressure filters Pressure filters feed the product to the filter at a pressure greater than that which would arise from gravity alone. This is the most common type of filter used in the processing of pharmaceutical products. In its simplest form, the metafilter · the rotary filter is a complex piece of equipment with many moving parts and is very expensive. In addition to the filter itself, ancillary equipment such as vacuum pumps, vacuum receivers and traps, slurry pumps and agitators are required. These rings, usually made of stainless steel, are approximately 15 mm in inside diameter, 22 mm in outside diameter and 0. The height of the projections and the shape of the section of the ring are such that when the rings are packed together and tightened on the drainage rod, channels are formed that taper from approximately 250 µm down to 25 µm. One or more of these packs is mounted in a vessel and the filter is operated by pumping in the slurry under pressure. In simple form, they consist of a cylindrical cartridge containing highly pleated material. This cartridge then fits in a metal supporting cylinder and the product is pumped under pressure into one end of the cylinder surrounding the filter cartridge. The filtrate is forced through the filter cartridge from the periphery to the inner hollow core, from where it exits through the other end of the support cylinder. The filter cartridges are often disposable and are good for applications where there is a low contaminant level. The pack of rings, therefore, serves essentially as a base on which the true filter medium is supported. The advantages of the metafilter can be summarized as follows: · It possesses considerable strength, and high pressures can be used with no danger of bursting the filter medium. The small surface area of the metafilter restricts the amount of solid that can be collected. This, together with the ability to separate very fine particles, means that the metafilter is used almost exclusively for clarification of liquids where the contaminant level is low. Furthermore, the strength of the metafilter permits the use of high pressures (up to 1. However, a large number of fibres can be contained in a surrounding shell to form a cartridge, which may have an effective filtration area greater than 2 m2. In use, the liquid to be treated is pumped through the cartridge in a circulatory system, so that it passes through many times. The great advantage of this mode of operation is that the high fluid velocity and turbulence minimize blocking of the membranes. Because the fluid flow is across the surface, rather than at right angles, this technique is known as cross-flow microfiltration. The method has been used for fractionation of biological products by first using a filter of pore size sufficient to let through all the molecules the same size as or smaller than those required, and then passing the permeate through a second filter that will retain the required molecules whilst allowing passage of smaller unwanted molecules. Blood plasma can be processed to remove alcohol and water and prepare concentrated purified albumin with this method. Principles of centrifugation If a particle (mass m; kg) spins in a centrifuge (radius r; m) at a velocity (v; m s-1), then the centrifugal force (F; N) acting on the particle equals mv2/r. The same particle experiences gravitational force (G; N) equal to m × g (where g is the gravitational constant). If the rotational velocity is taken to be dn, where n is the rotation speed (s-1) and d is the diameter of rotation (m), then C = 2.

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