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Examples include patients who now have to take only one tablet daily instead of one tablet three times daily because they are taking the osmotic pump form of the medication anxiety coach purchase nortriptyline 25mg otc. Not only does drug delivery improve convenience for patients but it also improves compliance as they adhere to treatment regimens that may have been too complex anxiety level scale order 25mg nortriptyline fast delivery. At this point the student should understand these concepts and understand the differences among immediate- anxiety numbness buy cheap nortriptyline line, modified- anxiety icd 9 buy nortriptyline 25 mg cheap, delayed-, extended-, and controlled-release delivery systems. You should also be able to differentiate between zero-order and first-order release kinetics as well as understand intrinsic dissolution rate and the driving force for dissolution. Understanding the effect of surface area and sink conditions on dissolution rate is critical and helps explain why drugs are so well absorbed after oral administration. Finally, the student should have an appreciation for the different roles that dissolution testing plays in the pharmaceutical sciences (a quality control versus predictive role) and understand how media properties such as viscosity, pH, lipids, and surfactants can affect dissolution. These tablets are orally delivered osmotic pumps that release drug through a laser-drilled orifice. Regulatory guidances recommend four dissolution apparatuses for modified-release dosage forms. Although the existing apparatuses are adequate for the intended purpose, equipment may require either modifications or completely new designs to accommodate these new release mechanisms. In contrast, disintegrating or eroding delivery systems pose the challenge of transferring the dosage form to different media without losing any of the pieces. In general, methods of agitation, changing the medium, and holding the dosage form in the medium without obstructing the release mechanism are relevant to drug testing. A challenging component of a dissolution test for a modified-release delivery system is changing the media to obtain a pH gradient or to simulate fed and fasted conditions. The ability to easily change the medium is the focus of commercially available dissolution equipment targeted for modified-release delivery systems, and several equipment designs are available. The cylinders can also be transferred to different media at specified times, automatically. Carstensen, Dissolution Technology, Academy of Pharmaceutical Sciences, Washington, D. Crison, Developing Dissolution Tests for Modified Release Dosage Forms: General Considerations. Understand the basis for transition-state theory and its application to chemical kinetics. The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors, such as temperature, humidity, and light, and to establish a retest period for the drug substance or a shelf life for the drug product and recommended storage conditions. Although the pharmaceutical scientist plays a critical role in determining the stability of pharmaceuticals, practicing pharmacists should be able to interpret this information for their patients. Pharmaceutical manufacturers routinely utilize the principles covered in this chapter; however, with the resurgence of pharmaceutical compounding, it is essential for practicing pharmacists to understand drug product stability as well. If a community pharmacist is asked to compound a prescription product, there are many factors that he or she must consider. The pharmacist must recognize that alterations in stability may occur when a drug is combined with other ingredients. For example, if thiamine hydrochloride, which is most stable at a pH of 2 to 3 and is unstable above pH 6, is combined with a buffered vehicle of, say, pH 8 or 9, the vitamin is rapidly inactivated. Even though pharmaceutical manufacturers label prescription and over-the-counter drug products with expiration dating to guide the patient/consumer in these matters, patients may store these products in a bathroom medicine cabinet where the humidity and temperature are higher than the typical storage place for medications. A community pharmacy practitioner should be able to understand this and advise patients on these matters. The experimental investigation of the possible breakdown of new drugs is not a simple matter. Applications of chemical kinetics in pharmacy result in the production of more stable drug preparations, the dosage and rationale of which may be established on sound scientific principles. Thus, as a result of current research involving the kinetics of drug systems, the pharmacist is able to assist the physician and patient regarding the proper storage and use of medicinal agents. This chapter brings out a number of factors that bear on the formulation, stabilization, and administration of drugs. Concentration, temperature, light, pH, and catalysts are important in relation to the speed and the mechanism of reactions and will be discussed in turn. According to the law of mass action, the rate of a chemical reaction is proportional to the product of the molar concentration of the reactants each raised to a power usually equal to the number of molecules, a and b, of the substances A and B, respectively, undergoing reaction. In the reaction aA + bB + = Products the rate of the reaction is 1 d[A] Rate = a dt 1 d[B] = = k[A]a [B]b b dt where k is the rate constant. The order with respect to one of the reactants, A or B, is the exponent a or b of that particular concentration term. Suppose that in this reaction, sodium hydroxide as well as water was in great excess and ethyl acetate was in a relatively low concentration. Each of the elementary reactions has a stoichiometry giving the number of molecules taking part in that step. Because the order of an elementary reaction gives the number of molecules coming together to react in the step, it is common to refer to this order as the molecularity of the elementary reaction. If, on the other hand, a reaction proceeds through several stages, the term molecularity is not used in reference to the observed rate law: One step may involve two molecules, a second step only one molecule, and a subsequent step one or two molecules. Hence, order and molecularity are ordinarily identical only for elementary reactions.
The delivery of these compounds from microemulsions was faster and showed deeper penetration into the skin than delivery from the macroemulsions anxiety chat room buy nortriptyline american express. The authors reviewed a number of studies on the delivery of drugs from the microemulsions anxiety research purchase nortriptyline in united states online. These reports anxiety symptoms electric shock nortriptyline 25mg on-line, including several patents anxiety symptoms feeling unreal buy nortriptyline 25 mg visa, dealt with the incorporation of fluorocarbons as blood substitutes and for the topical delivery of antihypertensive and anti-inflammatory drugs. Microemulsions are used in cosmetic science,58 foods, and dry cleaning and waxpolishing products. When the liquid is removed and only the framework remains, the gel is known as a xerogel. Hydrogels retain significant amounts of water but remain water-insoluble and, because of these properties, are often used in topical drug design. The diffusion rate of a drug depends on the physical structure of the polymer network and its chemical nature. In gels of lower hydration, the drug dissolves in the polymer and is transported between the chains. The gel mass may consist of floccules of small particles rather than large molecules, as found in aluminum hydroxide gel, bentonite magma, and magnesia magma, and the gel structure in these two-phase systems is not always stable. Such gels may be thixotropic, forming semisolids on standing and becoming liquids on agitation. On the other hand, a gel may consist of macromolecules existing as twisted, matted strands. Most inorganic gels can be characterized as two-phase systems, whereas organic gels belong to the single-phase class because the condensed matrix is dissolved in the liquid medium to form a homogeneous gelatinous mixture. Gels may contain water, and these are called hydrogels, or they may contain an organic liquid, in which case they are called organogels. Gelatin gel belongs to the former class, whereas petrolatum falls in the latter group. Swelling is measured as the increase in weight of gelatin strips in buffer solution at various times. The release of indomethacin from the gel followed Fickian diffusion over a period of 10 hr. The opposite of syneresis is the taking up of liquid by a gel with an increase in volume. Gels may also take up a certain amount of liquid without a measurable increase in volume, and this is called imbibition. The swelling of protein gels is influenced by pH and the presence of electrolytes. Ofner and Schott63 studied the kinetics of swelling of gelatin by measuring the increase in weight of short rectangular strips of gelatin films after immersion in buffer solutions as a function of time, t. A plot of the weight, W, in grams of aqueous buffer absorbed per gram of dry gelatin against t in hours gives the swelling isotherms. This phenomenon, known as syneresis, is thought to be due to the continued coarsening of the matrix or fibrous structure of the gel with a consequent squeezing-out effect. The reciprocal of the slope, 1/B = W, is the equilibrium swelling, that is, the theoretical maximum uptake of buffer solution at t. When the constants A and B are used to backcalculate the swelling, W, at several times and are compared with the experimental data, the higher deviations are found in the region of maximum curvature of the isotherms. Ofner and Schott63 attributed the deviations to the partially crystalline structure of gelatin. The penetration of the solvent into the crystalline region is slower and less extensive because this region is more tightly ordered and has a higher density (part b of the curve in. Gelatin is probably the most widely employed natural polymer in pharmaceutical products; it is used in the preparation of soft and hard gelatin capsules, tablet granulations and coatings, emulsions, and suppositories. Gelatin may interact with gelatin-encapsulated drugs or excipients by absorbing significant amounts of them, and some compounds may change the dissolution rate of soft gelatin capsules. Ofner and Schott64 studied the effect of six cationic, anionic, and nonionic drugs or excipients on the initial swelling rate and equilibrium swelling in gelatin. The cationic compounds reduced the equilibrium swelling, W, substantially, whereas the nonionic and anionic compounds increased it. The researchers suggested that the cationic additives such as quaternary ammonium compounds may cause disintegration and dissolution problems with both hard and soft gelatin capsules.
If the solution is dilute anxiety symptoms heart rate cheap nortriptyline 25 mg line, a2 can be replaced by c without introducing a significant error anxiety 7 year old son buy 25 mg nortriptyline otc. One of the more ingenious methods is due to McBain and Swain anxiety symptoms valium treats order 25mg nortriptyline mastercard,24 who literally fired a small microtome blade across a liquid surface so as to collect the surface layer anxiety symptoms upper back pain order nortriptyline 25 mg line. Analysis of the liquid scooped up and collected by the speeding blade agreed closely with that predicted by the Gibbs equation. Saturation adsorption of the surfactant has been Insoluble Monolayers and the Film Balance Insoluble monolayers have a fascinating history that goes back to before the American Revolution. In 1765, Franklin followed up this observation with an experiment on a half-acre pond in England and found that the application of 1 teaspoonful of oil was just sufficient to cover the pond and calm the waves. In 1899, Lord Rayleigh showed that when small amounts of certain slightly soluble oils were placed on a clean surface of water contained in a trough, they spread to form a layer one molecule thick (monomolecular layer). She carried out a series of experiments, which she summarized in a letter to Lord Rayleigh in January 1881. These and other early contributions in the area of surface phenomena are described in a series of papers by Giles and Forrester. The film thickness is equal to the length of the molecules standing in a vertical position on the surface when the molecules are packed in closest arrangement. Furthermore, if the molecular weight and the density of the spreading oil are known, the cross-sectional area available to the molecules should be easily computed. Schott27 stated that the film pressure, is an expansion pressure exerted on the monolayer that opposes the surface tension, 0, or contraction of the clean (water) surface. The surface-active molecules of the monolayer are thought to insert themselves into the surface of the water molecules of a film balance to reduce the resistance of the water surface to expansion. The presence of the surfactant molecules increases the ease of expansion, presumably by breaking or interfering with hydrogen bonding, van der Waals interaction, and other cohesive forces among the water molecules. In carrying out an experiment with the film balance, the substance under study is dissolved in a volatile solvent. The movable barrier is then moved to various positions in the direction of the float. The area of the trough available to the film at each position is measured, and the corresponding film pressure is read from the torsion dial. Langmuir, Adam, Harkins, and others made quantitative studies of the properties of films that are spread over a clear surface of the substrate liquid (usually water) contained in a trough. The film can be compressed against a horizontal float by means of a movable barrier. The force exerted on the float is measured by a torsion-wire arrangement similar to that employed in the ring tensiometer. Surface film pressure, for stearic acid and lecithin plotted as a function of cross-sectional area per molecule. The liquid expanded state (region L1) can be thought of as a bulk liquid state, but in two dimensions. Further compression of the film often leads to the appearance of an intermediate phase (region I) and then a less compressible condensed liquid state, region L2. This then gives way to the least compressible state, region S, where the film can be regarded as being in a two-dimensional solid state. This increase in with compression of the surfactant film results from surface-active molecules being forcibly inserted and crowded into the surface. This process opposes the natural tendency of the water surface to contract, and the surface tension decreases from 0 to . Finally, the molecules slip over one another, and the film breaks when it is greatly compressed. Phase changes that occur when a liquid film is spread at an interface and then compressed.
If the emulsion is of the w/o type anxiety 30002 purchase 25 mg nortriptyline with visa, the particles of dye will lie in clumps on the surface anxiety symptoms 6 weeks discount nortriptyline 25 mg on-line. Another test uses a pair of electrodes connected to an external electric source and immersed in the emulsion anxiety 4 year old nortriptyline 25 mg generic. If the external phase is water anxiety 025 purchase nortriptyline 25 mg with visa, a current will pass through the emulsion and can be made to deflect a voltmeter needle or cause a light in the circuit to glow. For a theory to be meaningful, it should be capable of explaining (a) the stability of the product and (b) the type of emulsion formed. Let us consider what happens when two immiscible liquids are agitated together so that one of the liquids is dispersed as small droplets in the other. Except in the case of very dilute oil-in-water emulsions (oil hydrosols), which are somewhat stable, the liquids separate rapidly into two clearly defined layers. Failure of two immiscible liquids to remain mixed is explained by the fact that the cohesive force between the molecules of each separate liquid is greater than the adhesive force between the two liquids. The cohesive force of the individual phases is manifested as an interfacial energy or tension at the boundary between the liquids, as explained in Chapter 15. When one liquid is broken into small particles, the interfacial area of the globules constitutes a surface that is enormous Pharmaceutical Applications An o/w emulsion is a convenient means of orally administering water-insoluble liquids, especially when the dispersed phase has an unpleasant taste. These agents are discussed in detail in Chapter 15, dealing with interfacial phenomena. The factor common to all three classes of emulsifying agent is the formation of a film, whether it be monomolecular, multimolecular, or particulate. On this basis, we can now discuss some of the more important theories relating to the stability and type of emulsion formed. To prevent coalescence or at least to reduce its rate to negligible proportions, it is necessary to introduce an emulsifying agent that will form a film around the dispersed globules. It is not unusual for a good emulsifying agent of this type to reduce the interfacial tension to 1 dyne/cm; we can therefore reduce the surface free energy of the system to approximately 1/60 of that calculated earlier. The reduction in surface free energy is of itself probably not the main factor involved. Ideally, such a film should be flexible so that it is capable of reforming rapidly if broken or disturbed. An additional effect promoting stability is the presence of a surface charge, which will cause repulsion between adjacent particles. In practice, combinations of emulsifiers rather than single agents are used most frequently today in the preparations of emulsions. In 1940, Schulman and Cockbain28 first recognized the necessity of a predominantly hydrophilic emulsifier in the aqueous phase and a hydrophobic agent in the oil phase to form a complex film at the interface. The combination of sodium cetyl sulfate and cholesterol leads to a complex film. Sodium cetyl sulfate and oleyl alcohol do not form a closely packed or condensed film. A hydrophilic Tween can be combined with a lipophilic Span, varying the proportions so as to produce the desired o/w or w/o emulsion. The bulky sorbitan heads of the Span molecules prevent the hydrocarbon tails from associating closely in the oil phase. When Tween 40 (polyoxyethylene sorbitan monopalmitate) is added, it orients at the interface such that part of its hydrocarbon tail is in the oil phase and the remainder of the chain, together with the sorbitan ring and the polyoxyethylene chains, is located in the water phase. It is observed that the hydrocarbon chain of the Tween 40 molecule is situated in the oil globule between the Span 80 chains, and this orientation results in effective van der Waals attraction. In this manner, the interfacial film is strengthened and the stability of the o/w emulsion is increased against particle coalescence. The same principle of mixed emulsifying agents can be applied in the use of combinations such as sodium stearate and cholesterol, sodium lauryl sulfate and glyceryl monostearate, and tragacanth and Span. The type of emulsion that is produced, o/w or w/o, depends primarily on the property of the emulsifying agent.
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