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The types of epithelial interfaces discount fluconazole online, the barriers they pose to drug absorption cheap fluconazole generic, and the routes and mechanisms of drug absorption across these interfaces buy 50 mg fluconazole with amex, are described below. They consist of one or more layers of cells, separated by a minute quantity of intercellular material. All epithelia are supported by a basement membrane of variable thickness, which separates the epithelium from underlying connective tissues. Epithelial interfaces are involved in a wide range of activities such as absorption, secretion and protection; all these major functions may be exhibited at a single epithelial surface. For example, the epithelial lining of the small intestine is primarily involved in absorption of the products of digestion, but the epithelium also protects itself from potentially harmful substances by the secretion of a surface coating of mucus. Epithelia are classified according to three morphological characteristics: • the number of cell layers; • the cell shape; • the presence of surface specializations. A single layer of epithelial cells is termed simple epithelium, whereas those composed of more than one layer are termed stratified epithelia. Stratified epithelia are found in areas which have to withstand large amounts of wear and tear, for example the inside of the mouth, or the skin. Epithelial cells may be, for example, squamous (flattened), columnar (tall), cuboidal (intermediate between squamous and columnar) and may contain surface specializations, such as cilia in the nasal epithelium and keratin in the skin. Detailed descriptions of the epithelia present in the various routes of drug delivery are given in the relevant chapters; a generalized summary is given here in Table 1. In man, goblet cells are scattered amongst cells of many simple epithelial linings, particularly of the respiratory and gastrointestinal tracts. Mucus is mainly composed of long, entangled glycoprotein molecules known as mucins, which vary in length from 0. Each monomer consists of a protein backbone, approximately 800 amino acids long, rich in serine, proline and threonine. Oligosaccharide side chains, generally up to 18 residues in length, composed of N- acetylgalactosamine, N-acetylglucosamine, galactose, fucose and N-acetylneuraminic acid are attached to the protein monomers. Its most important property is its viscoelasticity, which enables it to act as a mechanical barrier, but also allows it to flow. Mucus acts as a physical barrier through which drug molecules must diffuse, prior to reaching the absorbing surface. The rate of diffusion through the mucus will be dependent upon such factors as the thickness of the mucus layer, mucus viscosity and any interactions which may occur between the drug and mucus. In the respiratory tract, mucus is also involved in the process of mucociliary clearance, which contributes to the epithelial barrier properties by entrapping potentially hazardous substances, such as dust and microorganisms, within a viscoelastic mucus blanket. The mucus is then propelled by the claw-like tips of “hair-like” cilia towards the throat (movement occurs in a downwards direction from the nasal epithelium, or 7 in an upwards direction from the lungs), where the mucus and any entrapped particulates are either swallowed or expectorated. Although this process is beneficial if inhaled particles are hazardous, drug particles may also be cleared by this mechanism. Hydrophobic membranes and cell junctions Membranes surround all living cells and cell organelles. In the fluid mosaic model of the plasma membrane, the surfaces of the membrane are composed of tightly packed lipoidal molecules (including phospholipids, sphingolipids and sterols), interspersed with proteins. The proteins were originally thought to float in a sea of lipid, resulting in a rather ill-defined mixed membrane. Proteins in specific conformations act as structural elements, transporters of nutrients and environmental monitors. The plasma membrane of epithelial cells, in common with other cell types, is selectively permeable, allowing the penetration of some substances but not others. The construction of the membrane from amphipathic lipid molecules forms a highly impermeable barrier to most polar and charged molecules, thereby preventing the loss of most water-soluble contents of the cell. This selective permeability presents a physical barrier to drug absorption, limiting absorption to specific routes and mechanisms, as described below (see Section 1. A further important feature of epithelia for drug delivery is that the epithelial cells are bound together by several types of plasma membrane specializations, including desmosomes, gap junctions and junctional complexes (Figure 1. Desmosomes (macula adherens) are the commonest type of cell junction and are found at many intercellular sites, including cardiac muscle, skin epithelium and the neck of the uterus. At the desmosome, the opposing plasma membranes are separated by a gap in which many fine, transverse filaments are present. Desmosomes provide strong points of cohesion between cells and act as anchorage points for the cytoskeleton of each cell. Gap junctions (nexus) are broad areas of closely opposed plasma membranes, but there is no fusion of the plasma membranes and a narrow gap, of about 2 to 3 nm wide, remains. The “gap” is crossed by cytoplasmic filaments, which allow intracellular cytoplasm to transfer between cells.

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Place these two bottles in a thermostat maintained at 20°C until the contents have attained an equilibrium temperature order fluconazole 150mg overnight delivery, (2) Transfer 50 ml of the standard nitrating-acid to the insulated vessel and insert the motorised stirrer purchase fluconazole uk. Now buy fluconazole american express, start taking readings of the rise in temperature after each interval 1, 2, 3 and 5 minutes respectively, and (4) Plot a ‘calibration curve’ between the observed temperature-rise in a 3 minute interval Vs percent benzene present in cyclohexane. How does ‘thermoanalytical analysis’ give rise to various types of ‘thermograms’ that help in characterizing either a single or multicomponent system? Discuss, the fundamental theory of ‘thermogravimetric analysis’, and its instrumentation aspects in an elabo- rated manner. Attempt the following aspects of ‘differential thermal analysis’ : (a) Theory (b) Instrumentation (c) Methodology (d) Applications. Cl + NaCl + H2O Aniline Phenyl diazonium chloride It is interesting to observe here that the above reaction is absolutely quantitative under experimental parameters. Therefore, it forms the basis for the estimation of pharmaceutical substances essentially contain- ing a free primary amino function as already illustrated earlier. Thus, the liberated iodine reacts with starch to form a blue green colour which is a very sensitive reaction. Besides, the end-point may also be accomplished electrometrically by adopting the dead-stop end-point technique, using a pair of platinum electrodes immersed in the titration liquid. A few typical examples are described below to get an indepth knowledge about sodium nitrite titrations. Theory : The nitrous acid, generated on the introduction of sodium nitrite solution into the acidic reaction mixture, reacts with the primary amino group of sulphanilamide quantitatively, resulting into the formation of an unstable nitrite that decomposes ultimately with the formation of a diazonium salt. The diazonium salt thus produced is also unstable, and if the reaction mixture is not maintained between 5-10°C, it shall undergo decomposition thereby forming phenol products which may react further with nitrous acid. Add to it 25 g of crushed ice, and titrate slowly with sodium nitrite solution, stirring vigorously, until the tip of the glass rod dipped into the titrated solution immediately produces a distinct blue ring on being touched to starch-iodide paper. The titration is supposed to be complete when the end-point is deducible after the resulting mixture has been allowed to stand for 1 minute. Theory : The assay of calcium aminosalicylate is based upon the reaction designated by the following equation : Therefore, 344. Pipette 50 ml into a conical flask, cool to below 15°C (in ice-bath) and titrate gradually with 0. Theory : The estimation is based on the fact that isocarboxazid undergoes rapid cleavage in acidic medium to produce benzylhydrazine. The latter reacts with nitrous acid to yield the corresponding diazonium salt quantitatively. The contents of the flask are shaken thoroughly and continuously until a distinctly visible blue colour is obtained when a drop of the titrated solution is placed on a starch-iodide paper 5 minutes after the last addition of the 0. Why is it necessary to perform ‘sodium nitrite titrations’ invariably in an acidic medium? Based on the ‘diazotization reaction’ how would you carry out the assay of the following ‘drug substances’ : (i) Isocarboxazid (ii) Phthalylsulphathiazole (iii) Sulphamelthoxazole (iv) Primaquine phosphate. These products of reaction are produced quantitatively and are mostly water-insoluble in characteristics ; and more interestingly they take place in an acidic medium. As it has been discussed earlier, iodine cannot be used directly as an oxidizing agent in such type of assays, whereas the liberated iodine quantitatively produced by the oxidation of iodide with bromine (excess) may be assayed by titrating against sodium thiosulphate solution. Procedure : Weigh 3 g of potassium bromate and 15 g of potassium bromide in a beaker and dissolve with water. Add to it 5 ml of hydrochloric acid, moisten the glass-stopper with water and insert the stopper in the flask. Now, add 5 ml of potassium iodide solution, again lace the stopper and allow the resulting mixture to stand for 5 minutes in the dark. Warm the solution to about 75°C, add 2 drops of methyl orange solution and continue the titration gradually while swirling the contents of the flask thor- oughly after each addition. If the colour of the solution is still red, continue the titration dropwise and with constant stirring until the red colour of the indicator is discharged completely. Repeat an operation without the pharmaceutical substance (blank titration) ; thus the difference between the titrations represents the amount of bromine required by the ethacrynic acid. Cognate Assays A number of pharmaceutical substances may be determined quantitatively by titration with bromine as given in Table 13. Transfer the solution quantitatively into a 1 litre volumetric flask and make up the volume to the mark. Mix the contents thoroughly and allow it to stand for 5 minutes with its stopper in position. Carry out a blank run using the same quantities of the reagents and incorporate the necessary corrections, if any. Mephenesin Theory : Mephenesin undergoes oxidation with bromine to yield a dibromo derivative as expressed in the following equation : BrO – + 6e + 6H+ → Br– + 3H O...

Question of Quality It has now been established beyond any reasonable doubt that quality of a drug product cannot simply be ensured by inspection or analysis discount fluconazole 50 mg with mastercard, but a control system has to be built into cheap 200 mg fluconazole visa, from the very beginning of manufac- ture of a drug cheap 50 mg fluconazole otc. Besides effective quality control measures exercised in every aspects of production including environment, screening of raw materials, process controls, intermediate shelf-life of finished products the most important aspect is to assess the bioavailability of the active principle. Difference in bioavailability, particularly in drugs with low solubilty, as ascertained by blood level attainment studies, appears to be caused by a number of formulation variables, namely : particlesize, crystalline structure, binding or disintegrating agent, excipient etc. For example : the rate of dissolution of the drug in tablet or a capsule in the gastrointestinal fluids. Clinical Efficacy of Drugs Medical scientists mainly rely on the measurement of bioavailability of a drug as a positive indicator of therapeutic equivalence, because clinical efficacy for orally administered drugs depends on the degree of absorption and the presence of the active ingredient in the blood stream. Technical information based on in vivo standards and specifications are generally incorporated in vari- ous official compendia. Hence, in order to record a legitimate assessment of bioavailability, in vivo test is an absolute necessity and the relative data obtained therefrom should form an integral part of the standard specifi- cations in the offcial standard. Hence, a regular feed back of relevant informa- tion on such adverse reactions from the medical practitioners to the appropriate regulatory authorities and the concerned manufacturers would not only help to intensify better safety measures but also widen the scope to improve drug-design by meticulous research scientists all over the world. They are : Example 1 : Aspirin—Increased gastric damage and subsequent bleeding caused by some aspirin fomulations have been specifically attributed to the slowly dissolving aspirin particles in the stomach. However, both effervescent and highly buffered dosage forms (antacid-aspirin-tablet), which help in maintaining the aspirin in solution, have been found to minimise gastro-intestinal toxicity. The physical constants essentially include the melting point, boiling point, refractive index, weight per millilitre, specific optical rotation, light absorption, viscosity, specific surface area, swelling power, infra-red absorption, and the like. However, the most specific and reliable are the chemical tests which may be categorized separately under tests for inorganic substances and organic substances. The former may be carried out by well defined general quantitative inorganic analysis and the latter by specific reactions of one or more of the functional moieties present in a drug molecule. These physical constants will be discussed briefly with typical examples as under : 1. Melting Point It is an important criterion to know the purity of a substance ; however, it has a few limitations. The accuracy and precision of melting point is dependent on a number of factors such as—capillary size, sample size, initial temperature of heating-block and the rate of rise of temperature per unit time (minutes). Keeping in view the different manufacturing processes available for a particular drug the melting point has a definite range usually known as the melting range. Mestranol 146 154 Thus the melting range takes care of the variance in manufacture together with the storage variance over a stipulated period of time. Boiling Point It is also an important parameter that establishes the purity of a substance. Depending on the various routes of synthesis available for a substance a boiling point range is usually given in different official compendia. Refractive Index It is invariably used as a standard for liquids belonging to the category of fixed oils and synthetic chemicals. Weight Per Millilitre Weight per millilitre is prevalent in the Pharmacopoeia of India for the control of liquid substances, whereas Relative Density (20°/20°) or Specific Gravity is mostly employed in the European Pharmacopoeia. Specific Optical Rotation As pharmacological activity is intimately related to molecular configuration, hence determination of specific rotation of pharmaceutical substances offer a vital means of ensuring their optical purity. Morphine Hydrochloride – 112° – 115° Calculated with reference to the dried substance in a 2% w/v soln. Light Absorption The measurement of light absorption both in the visible and ultraviolet range is employed as an authentic means of identification of offcial pharmaceutical substances. Viscosity Viscosity measurements are employed as a method of identifing different grades of liquids. Specific Surface Area The surface area of powders is determined by subsieve-sizer which is designed for measurement of average particle sizes in the range of 0. Swelling Power The swelling power of some pharmaceutical products are well defined. Examples : (i) Isphagula Husk : When 1 g, agitated gently and occasionally for four hours in a 25 ml stoppered measuring cylinder filled upto the 20 ml mark with water and allowed to stand for 1 hour, it occupies a volume of not less than 20 ml and sets to a jelly. Infrared Absorption Measurement and subsequent comparison of the infrared spectrum (between 4000-667 cm–1) of compounds with that of an authentic sample has recently become a versatile method for the identification of drugs having widely varying characteristics. Examples : Infrared spectroscopy is employed to compare samples of chloramphenicol palmitate (biologically active form) recovered from chloramphenicol palmitate mixture vis-a-vis an artificially prepared mixture of authentic sample consisting 10 per cent of the ‘inactive polymorph’. Miscellaneous Characteristics A large number of miscellaneous characteristics are usually included in many official compendia to ascertain the purity, authenticity and identification of drugs—including : sulphated ash, loss on drying, clarity and colour of solution, presence of heavy metals and specific tests. Sulphated Ash Specifically for the synthetic organic compounds, the Pharmacopoeia prescribes values for sulphated ash. The sulphated ash is determined by a double ignition with concentrated sulphuric acid. The method is one of some precision, and provides results which are rather more reproducible than those obtained by simple ignition. Loss on Drying Loss on drying reflects the net weight of a pharmaceutical substance being dried at a specified tempera- ture either at an atmospheric or under reduced pressure for a stipulated duration with a specific quantity of the substance. Clarity and Colour of Solution When a pharmaceutical substance is made to dissolve at a known concentration in a specified solvent it gives rise to a clear solution that may be either clear or possess a definite colouration.

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Smaller nanoparticles were obtained at an ethanol/water ratio that matched the solubility parameter of gliadin and in which the protein was in the expanded con- formation quality fluconazole 150mg. Protein nanoparticles can be rigidized by cross-linking using glutaraldehyde or glyoxal cheap fluconazole 200 mg overnight delivery, and an increase in cross-linker generally decreases particle size due to the formation of denser particles (48) order fluconazole uk. In case of albumin, it was found that the non–cross- linked protein nanoparticles coalesced to form a separate phase (45). Therefore, cross-linking stabilizes the protein nanoparticles and, in addition, reduces enzy- matic degradation and drug release from the protein nanoparticles (42,48). How- ever, it is essential to remove the cross-linkers as completely as possible due to their known cytotoxic properties (1). Furthermore, the cross-linkers can also affect the sta- bility of drugs, particularly protein drugs during entrapment in the nanoparticles. Nanoparticles prepared using hydrophobic proteins generally require surfac- tants to stabilize the nanoparticles (41). Poloxamer was used to improve the solu- bility of legumin in the aqueous phase and stabilize the nanoparticles during phase separation (41). An increase in surfactant concentration increased the yield without appreciably altering the particle size (41). Drugs can be loaded by either surface adsorption onto preformed nanoparticles or entrapping the drug during the prepa- ration of nanoparticles. However, the encapsulation efficiency depends on the drug properties and the drug/polymer ratio, among other factors. Emulsion/Solvent Extraction In this method, an aqueous solution of the protein is emulsified in oil by using a high-speed homogenizer or ultrasonic shear and the nanoparticles are formed at the w/o interface (Fig. Surfactants, such as phosphatidyl choline or Span 80, are included as stabilizers to produce nanoparticles (57,58). Olive oil was used as an oil phase and was slowly added to the aqueous protein solution under mechanical stirring, followed by ultrasonication. The cross-linker glutaraldehyde was added to the emulsion to obtain nanoparticles in the size range of 100 to 800 nm. The protein concentration and the aqueous-phase volume (w/o) ratio influenced the particle size. An increase in w/o phase volume ratio increased the particle size of nanoparticles. In this method, the aqueous protein solution was emulsified with castor oil by using Span 80. The resultant emulsion was then added dropwise to heated (120◦C–140◦C) castor oil with stirring to evaporate the aqueous phase. Albumin concentration, emulsification time, and the rate of emul- sion addition to castor oil affected the particle size. Furthermore, it is difficult to completely remove the oil phase or the organic solvent from the final formulation. Complex Coacervation Since proteins are amphoteric with a large number of charged functional groups, they can be made cationic or anionic by adjusting the pH below or above the pI of the protein, respectively. The charged protein can then undergo electrostatic inter- actions with other polyelectrolytes (Fig. Salts such as sodium sulfate can be used to induce desolvation of the local water environment in the polyelec- trolyte complex (200–750 nm). Furthermore, the nanoparticles can be stabilized by cross-linking with glutaraldehyde. Endolysomotropic agents and other drugs can also be coencapsulated during complex coacervation. In the first step, gelatin nanoparticles were pre- pared by coacervation by using acetone as a desolvating agent. These nanoparticles were in the size range of 183 to 288 nm, with a neutral or slightly positive zeta-potential. Various steps involved in the opsoniza- tion and clearance of particles from the blood are shown in Figure 6. Opsonization is the process by which a foreign organism or particle becomes covered with the so-called opsonin proteins (65). There are more than 3700 plasma proteins which compete to bind to the nanoparticle surface (66). Initially, albumin and fibrinogen dominate the particle surface but are subsequently displaced by higher affinity pro- teins including immunoglobulins (IgM and IgG), laminin, fibronectin, C-reactive protein, and type I collagen (65,66). These bound proteins determine the subse- quent particle uptake by various cells of the immune system and their interac- tion with other blood components. Van der walls, electrostatic, and hydrophobic/hydrophilic forces are involved in the binding of opsonins to nanoparticles (65). Generally, neutral and hydrophilic particles undergo much lower opsonization than do charged and hydrophobic particles (68). Furthermore, the complement proteins involved in opsonization are specific to the surface functional groups in the nanoparticles (69). The particle size strongly influences the quality and quantity of proteins adsorbed on the nanoparticle surface.