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One of the first references to the determination of the freezing point of blood and tears (as was necessary to make solutions isotonic with these fluids) is that of Lumiere and Chevrotier arthritis nos icd 9 90mg etoricoxib with visa,32 in which the values of -0 arthritis in lower back uk buy generic etoricoxib 90mg. Following work by Pedersen-Bjergaard and coworkers bad arthritis in back etoricoxib 90mg with amex,33 rheumatoid arthritis bursitis cheap 90 mg etoricoxib overnight delivery,34 however, it is now well established that -0. As a result of this similarity between compounds of a given ionic type, a table can be arranged listing the L value for each class of electrolytes at a concentration that is isotonic with body fluids. It will be observed that for dilute solutions of nonelectrolytes, Liso is approximately equal to Kf. The selection of L values in this concentration region is not sensitive to minor changes in concentration; no pretense to accuracy greater than about 10% is implied or needed in these calculations. The Liso values can also be used for calculating sodium chloride equivalents and Sprowls V values, as discussed in subsequent sections of this chapter. The calculations involved in the cryoscopic method are explained best by an example. To make this solution isotonic with blood, sufficient sodium chloride must be added to reduce the freezing point by an additional 0. In the freezing point table, it is also observed that a 1% solution of sodium chloride has a freezing point lowering of 0. In the class I methods, sodium chloride or some other substance is added to the solution of the drug to lower the freezing point of the solution to -0. Under this class are included the cryoscopic method and the sodium chloride equivalent method. The preparation is then brought to its final volume with an isotonic or a buffered isotonic dilution solution. Sodium Chloride Equivalent Method A second method for adjusting the tonicity of pharmaceutical solutions was developed by Mellen and Seltzer. The values vary somewhat with concentration, and those in the table are for 1% to 3% solutions of the drugs in most instances. The quantity of the drug is multiplied by its sodium chloride equivalent, E, giving the weight of sodium chloride to which the quantity of drug is equivalent in osmotic pressure: Ephedrine sulfate: 1. If one desired to use dextrose instead of sodium chloride to adjust the tonicity, the quantity would be estimated by setting up the following proportion. It is recognized that thimerosal becomes less stable in eye drops when a halogen salt is used as an "isotonic agent". Reader38 found that mannitol, propylene glycol, or glycerin-isotonic agents that did not have a detrimental effect on the stability of thimerosal-could serve as alternatives to sodium chloride. Stimulated by the need to adjust the pH in addition to the tonicity of ophthalmic solutions, White and Vincent39 developed a simplified method for such calculations. Suppose that one wishes to make 30 mL of a 1% solution of procaine hydrochloride isotonic with body fluid. First, the weight of the drug, w, is multiplied by the sodium chloride equivalent, E: 0. The Liso for such a compound, a salt of a weak acid and a strong base (a 1:1 electrolyte), is 3. However, from the work of Reader38 we know that sodium chloride interacts with mercury compounds such as thimerosal to reduce the stability and effectiveness of this preparation. When more than one ingredient is contained in an isotonic preparation, the volumes of isotonic solution, obtained by mixing each drug with water, are additive. If a small amount of a strong acid or base is added to water or a solution of sodium chloride, the pH is altered considerably; such systems have no buffer action. In this chapter, the theory of buffers was introduced as were several formulas for making commonly used buffers. Pharmaceutical buffers must usually be made isotonic so that they cause no swelling or contraction of biological tissues, which would lead to discomfort in the patient being treated. The Sprowls Method A further simplification of the method of White and Vincent was introduced by Sprowls. The method as described by Sprowls40 is further discussed in several reports by Martin and Sprowls. Pedersen-Bjergaard, the Preparation of Solutions Isosmotic with Blood, Tears, and Tissue (Danish Pharmacopeia Commission), Vol. Describe what a distribution coefficient and partition coefficient are and their importance in pharmaceutical systems. Generally speaking, the solubility of a compound depends on the physical and chemical properties of the solute and the solvent as well as on such factors as temperature, pressure, the pH of the solution, and, to a lesser extent, the state of subdivision of the solute. Of the nine possible types of mixtures, based on the three states of matter, only liquids in liquids and solids in liquids are of everyday importance to most pharmaceutical scientists and will be considered in this chapter. For the most part, this chapter will deal with the thermodynamic solubility of drugs. The thermodynamic solubility of a drug in a solvent is the maximum amount of the most stable crystalline form that remains in solution in a given volume of the solvent at a given temperature and pressure under equilibrium conditions. Thermodynamic equilibrium is achieved when the overall lowest energy state of the system is achieved.

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Creep compliance curves of Soft White Paraffin (British Pharmacopoeia) at three temperatures arthritis pain under knee cap buy 90mg etoricoxib mastercard. Three curves are characteristic of the crystalline bonding and the interaction of crystalline and amorphous material that constitute petrolatum arthritis in neck causing ear pain purchase etoricoxib master card. Another dynamic rheologic method that does not disturb the structure of a material is that of oscillatory testing arthritis medication limbrel order etoricoxib 60 mg without prescription. The shearing stress produced by the oscillating force in the membrane of the apparatus results in a shear rate proportional to the surface velocity of the material arthritis in fingers and toes safe 120 mg etoricoxib. The viscoelastic behavior of materials obtained by oscillatory shear measurements can be analyzed by an extension of the Maxwell spring-and-dashpot model. Steady shear methods involving rotational viscometers tend to break down materials under analysis, and although they yield useful data on thixotropy and yield stress, for exam- 487 ple, they do not provide information about the original structure and bonding in pharmaceutical and cosmetic semisolids. Viscoelastic analysis performed by creep or oscillatory methods is particularly useful for studying the structure of liquid and semisolid emulsions and gels. Radebaugh and Simonelli28 studied the viscoelastic properties of anhydrous lanolin, which were found to be a function of strain, shear frequency, shear history, and temperature. The energy of activation, Ev, was calculated for the structural changes of the lanolin sample, which was found to undergo a major mechanical transition between 10 C and 15 C. Rather than a sharp change from a rubbery to a glasslike state, however, anhydrous lanolin appeared to change to a state less ordered than glass. The rheometer introduces a definite deformation into the sample at a specified rate and at a chosen temperature. For the design of mucolytic agents in the treatment of bronchitis, asthma, and cystic fibrosis, viscoelastic methods are also of value in the analysis of sputum. Other biologic fluids such as blood, vaginal material, and synovial fluids may be analyzed by viscoelastic test methods. The unsteady shear to which synovial fluids are subjected in the body during the movement of leg and arm joints requires the elastic properties of these fluids, in addition to viscous properties that are observed only in steady shear. Thurston and Greiling29 used oscillatory shear to analyze cases of noninflammatory and inflammatory joint disease associated with arthritis. The macromolecule hyaluronic acid is primarily responsible for the high viscosity and non-Newtonian character of synovial fluid and gives it simple Newtonian rather than the desired non-Newtonian properties. Workers in the food industry have long tested products such as butter, chocolate, mayonnaise, and bread dough for proper consistency during manufacture, packaging, and end use. Sensations in the mouth, between the fingers, and on the skin are important considerations for manufacturers of foods, cosmetics, and dermatologic products. Kostenbauder and Martin31 assessed the spreadability of ointments in relation to their rheologic properties. In consultation with dermatologists, they divided the products into three classes. Thus, although a product may be sufficiently thixotropic in its container, this property can be lost following application to the skin. They used a panel to differentiate textural parameters and established rheologic methods for use in industry as control procedures for maintaining uniform skin feel and spreadability of dermatologic products. They found that a panel of untrained subjects could accurately assess the consistency of a material by the use of only three attributes: smoothness, thinness, and warmth. Smoothness was related to a coefficient of friction and thinness to non-Newtonian viscous parameters that could be measured with appropriate instruments. The characteristic of warmth was found to be sufficiently complex to require further study. The addition of sodium chloride, glycerin, or propylene glycol resulted in increased apparent viscosities of the vehicles. Polymer solutions can be used in ophthalmic preparations, as wetting solutions for contact lenses, and as tear replacement solutions for the condition known as dry eye syndrome. For high-polymer solutions, the viscosity levels off to a zero-shear viscosity (a high viscosity) at low shear rates. The viscosity decreases as the shear rate is increased because the normally twisted and matted polymer molecules align in the streamlined flow pattern and exhibit pseudoplasticity or shear thinning. The low viscosity at high shear rates produces lubrication during blinking, and the high viscosity at zero shear rate prevents the fluid from flowing away from the cornea when the lids are not blinking. Using a computer-controlled Couette viscometer, they studied the rheologic properties of eight commercial tear substitutes, together with 0. For five of the commercial products, the viscosity was independent of shear rate; thus, these products behaved as Newtonian liquids. Only the commercial product Neo-Tears and the two noncommercial sodium hyaluronate solutions showed the desired pseudoplastic behavior. For Neo-Tears the viscosity at high shear rate, 1000 sec-1, was 3-fold that at zero shear. Therefore, sodium hyaluronate appears to be an excellent candidate as a tear replacement solution.

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The muscle groups of the serratus anterior posteriorly and the intercostals medially and anteriorly are divided rheumatoid arthritis fingers order 60 mg etoricoxib with visa. Care should be taken at the anterior end of the incision rheumatoid arthritis ulnar drift buy online etoricoxib, where the internal mammary artery runs and may be transected arthritis medication for older dogs order etoricoxib 90mg on-line. The parietal pleura is then opened arthritis genetic cheap etoricoxib line, taking care to avoid the internal mammary artery adjacent to the sternal border. Excision of the xiphoid cartilage may be necessary if this is large and intrusive, and can be done with heavy scissors. Split section (bisection) of the sternum is carried out with a saw (either oscillating or a braided-wire Gigli saw) or a Lebsche knife, commencing from above and moving downwards. This is an important point to avoid inadvertent damage to vascular structures in the mediastinum. In addition, be aware of the possible presence of the large transverse communicating vein, which may be found in the areolar tissue of the suprasternal space of Burns, and must be controlled. Median sternotomy Extension into the neck Following definitive manoeuvres, the anterolateral thoracotomy is closed in layers over one or two large-bore intercostal tube drains and after careful haemostasis and copious lavage. It is advisable to close the pericardium with an absorbable suture to avoid adhesion formation. Care should be taken to ligate the internal mammary arteries, and to ensure haemostasis prior to closure. The incision is particularly effective in those situations where it is important to achieve rapid access to the opposite side of the chest, especially posteriorly, such as for: Transmediastinal injury Lung injury Injury on the right, where aortic control may be necessary. A median sternotomy with extension of the incision into the neck will provide more rapid and efficient exposure of injury in this region. It is more time-consuming in approach and closure, since the bulkier muscle groups of the posterolateral thorax are traversed, and scapular retraction is necessary. This is a combination of an anterolateral thoracotomy, a partial sternotomy and an infra- or supraclavicular incision with resection or dislocation of the clavicle (Figure 6. These are applied according to the best incision for the particular injury suspected (based on the entrance and exit wounds, the trajectory and the most likely diagnosis from clinical examination), and may be extended in various ways according to need. The incision is placed in the fifth intercostal space through muscle, periosteum and parietal pleura from the costochondral junction anteriorly to the mid-axillary line laterally following the upper border of rib, and care is taken to avoid the internal mammary artery. This incision can be extended as a bilateral incision requiring horizontal division of the sternum and ligation of the internal mammary vessels bilaterally. It affords excellent access to both pleural cavities, pericardial cavity and even the abdominal cavity if required. The incision also may be extended cranially in the midline by dividing the sternum for penetrating wounds involving the mediastinal structures. The same incision may be employed on the right side in hypotensive patients with penetrating right chest trauma in whom massive blood loss or air embolism is suspected. The median sternotomy affords the best exposure to the anterior and middle mediastinum, including the heart and great vessels, and is typically advocated for penetrating wounds, particularly of the upper chest between the nipples. This can be extended supraclavicularly for access to control subclavian and brachiocephalic vascular injuries. Cardiac bleeding points on the ventricle are initially managed with digital pressure, and those on the atria and great vessels by partially occluding vascular clamps. If the heart is beating, repair should be delayed until initial resuscitation measures have been completed. Foley catheters may be used to temporarily control haemorrhage prior to definitive repair in the emergency department or operating theatre. Once it has been placed, great care should be taken not to exert too much traction on the catheter as it will easily tear out, making the hole dramatically bigger. Suturing of the right ventricle requires the placement of Teflon pledgets, which are utilized selectively on the left ventricle using a horizontal mattress suture under the coronary vessels to avoid trauma to or occlusion of the coronary vessels. Low-pressure venous and atrial wounds can be repaired with simple continuous sutures. Posterior wounds are more difficult as they necessitate elevation of the heart before their closure, which can lead to further haemodynamic compromise. With large wounds of the ventricle or inaccessible posterior wounds, temporary digital inflow occlusion might be necessary to facilitate repair. After initial repair, fluids are best slowed down to limit further bleeding (the concept of hypotensive resuscitation), aiming for critical organ perfusion while minimizing additional haemorrhage. The patient is best transferred to the operating theatre, where repair of the injury and closure of the access procedure is carried out under controlled circumstances with adequate resources. It is important to identify the phrenic nerve prior to opening the pericardium at least 1 cm anterior to this structure. The pericardial incision is initiated using either a knife or the sharp point of a pair of scissors, and blood and clots are evacuated. With localized bleeding sites, control can be achieved with vascular clamps placed across the affected segment. The affected segment is then dealt with, preferably in controlled circumstances in the operating theatre by local oversewing, segmental resection or pulmonary tractotomy. Pulmonary tractotomy is a means of controlling tracts that pass through multiple lung segments where the extent of injury precludes pulmonary resection. It is a means of non-anatomical lung preservation in which linear staplers are passed along both sides of the tract formed, and the lung is divided to allow blood vessels and airways in the bases to be repaired; the divided edges are then oversewn. With massive haemorrhage from multiple or indeterminate sites, or widespread destruction of lung parenchyma the chest 91 leaving large areas of non-viable tissue, hilar clamping with a large soft vascular clamp across the hilar structures occluding the pulmonary artery, pulmonary vein and main-stem bronchus is employed until a definitive surgical procedure can be performed.

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By far arthritis in big toe purchase etoricoxib 90 mg line, the most common method employed is that of lyophilization rheumatoid arthritis pathology buy etoricoxib 60mg low price, which is also known as freeze-drying arthritis treatments at home best order etoricoxib. There exist a variety of other potentially useful technologies such as foam drying arthritis in neck symptoms purchase 90mg etoricoxib mastercard, which will not be described here. In the first, the water in a solution of the biopharmaceutical agent is converted to ice. This freezing step is typically performed in the temperature range of -45 C to -10 C for 2 to 5 hr. The final procedure (secondary drying) involves removal of most of the remainder of the unfrozen water down to 1% to 4% as the temperature is increased from the previous process to 4 C to 50 C for 5 to 15 hr. In contrast, spray drying is a continuous process and involves drying from the liquid state. This is generally considered to be the most problematic aspect of the procedure given the presence of the air/water interface, a potential site of protein degradation and aggregation. The latter water content is typically somewhat greater than that produced by lyophilization and may result in greater degradation of the macromolecular drug or vaccine upon storage. In spray-freeze drying, the atomization and freezing is carried out in a solvent such as liquid nitrogen followed by macromolecule/vaccine drying. Because it is so much more commonly employed, we will consider lyophilization in more detail. In the initial freezing step, most biomolecules form amorphous solids (in contrast to many small molecules solutes which may crystallize). In general, primary drying is performed 2 C to 3 C below Tg (Tee Gee prime), the glass transition temperature of the freeze concentrate. The glass transition temperature (Tg for a pure solid) refers to the softening of a glasslike solid to form a viscous liquid state, which permits increased molecular mobility and subsequently enhanced degradation. One potential problem occurs because of the concentration that occurs during freezing. A buffer-like sodium phosphate may crystallize causing a shift of several units to lower pH, a potentially degradative condition. Thus, phosphates are usually not 555 employed (although small amounts may be acceptable). In general, a minimal weight ratio of buffer to other solutes is used to minimize crystallization-induced pH shifts as well as prevent large reductions in Tg and therefore increased solute mobility. During primary drying (ice sublimation), Tg reflects the temperature at which the conversion from a glassy to rubbery solid state occurs. As the material is dried it can also undergo a loss of structure that is referred to as cake "collapse" with the temperature at which this occurs designated the collapse temperature (Tc). During secondary drying as the unfrozen water is removed, this phase change is seen hear the Tg. As one moves above a glass transition temperature, the mobility and reactivity of the macromolecule or its complexes increase. Thus, knowledge of this property is one key to preparing a stable, lyophilized formulation. To create a stable dry formulation of a biotechnologybased drug, all of the above must be considered in its creation. Besides optimization of the lyophilization cycle, such formulations almost always contain excipients. Bulking agents such as mannitol or glycine are often employed for "elegance" and to prevent "blow-out" in which the dry cake can be expelled into the freeze dryer. Bulking agents are often chosen for their crystallinity and their high eutectic temperature to facilitate rapid, easy drying. Crystallinity is typically evaluated by a combination of polarized light microscopy (to detect birefringence), x-ray powder diffraction, and calorimetry. Buffers are often included for pH control although care must be taken that their crystallization does not produce large and potentially destructive pH shifts. In addition, compounds such as hydroxyethyl starch can be used to raise the Tc of the product. Especially critical for biopharmaceuticals, stabilizers are often necessary to provide a sufficiently robust formulation. The complex relationship between water content, molecular mobility, and the physical and chemical degradation of dried macromolecular systems can make the selection and optimization of stabilizers especially challenging. There are, however, several generally accepted principles for successful stabilization 556 of biomolecules in the solid state. A well-known example of this problem involves the use of sucrose, often a highly effective stabilizer. At low pH, this disaccharide can be hydrolyzed to reducing sugars, which can covalently interact with proteins. Third, as mentioned previously, the formulation should not permit selective buffer crystallization and consequent pH shifts. Many macromolecules and viruses and other biological entities are often pH sensitive with losses in biological properties upon exposure to extremes of pH. Finally, it is very clear that low water content is often essential for optimal stabilization in dried formulations. The formulation of an ice/water interface may result in adsorption of proteins and other amphipathic macromolecules which can be significantly destabilizing. This is at least partially due to the forces exerted by the surface on macromolecules due to the multipoint nature of the contacts between the surface and the drug or vaccine. The presence of stabilizers may reduce such destabilizing effects but the mechanisms are incompletely understood. The preferential hydration (solute exclusion) mechanism discussed previously may be operative at this level.

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