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The standards for pharmaceutical chemicals and their respective dosage forms buy generic bupropion 150mg online, as laid down in generic 150mg bupropion fast delivery, various Official Compendia fulfil broadly the following three cardinal objectives order 150mg bupropion with amex, namely : (a) Broad-based highest attainable standard, (b) Biological response versus chemical purity, and (c) Offical standards versus manufacturing standards. A wide variation of active ingredients ranging between 90% in one sample and 110% (± 10 per cent limit) in another sample could invariably be observed. Therefore, it has become absolutely essential to lay down definite standards so as to ensure that : • Different laboratories may produce reasonably reproducible products. Examples : (i) Substances to be stored in well-closed, light-resistant containers e. It is a well-known fact that a pharmaceutical substance can be prepared by adopting different routes of synthesis based upon the dynamic ongoing research in the field of organic-reaction-mechanisms. Relentless efforts are exerted vigorously by reputed research laboratories across the world to look for shorter routes of synthesis bearing in mind the cost-effectiveness of the final product. Nevertheless, the latter product is more in demand because it is completely devoid of bromine residues in the final product. During the process of manufacture an unavoidable criterion is the loss of active ingredients. Therefore, all Official Standards for pharmaceutical chemicals and dosage forms should accomodate such losses caused due to loss in manufacture, unavoidable decomposition and storage under normal conditions for a stipulated period. Official standards with regard to dosage form and packs, preservation and prevention from contamination in a variety of pharmaceutical products, such as eye-drops, multidose injections and antiseptic creams (external application) that may be prone to spoilage with prolonged repetitive usage should be well defined. Hence, all pharmaceutical chemicals and finished products must rigidly conform to the laid-out standards in a particular country and are subjected to various checks at different levels either by Government/State owned drug testing laboratories or by Government/State approved drug testing laboratories. Official Compendia for pharmaceutical substances usually include the following parameters, namely : • Description of the Drug or Finished Product • Identification Tests • Physical Constants • Assay of Pharmaceutical Substances • Assay of Principal Active Ingredients in Formulated Dosage Forms • Limit Test • Storage Conditions 1. In other words, the accuracy and significance of measurements may be solely limited by the sampling process. Unless and until the sampling process is performed properly, it may give rise to a possible weak link in the interpretation of the analytical results. However, a good deal of the wisdom of the analyst supported by the application of statisical results and wealth of experience may go a long way in achieving reasonably accurate and reproducible results. Sampling Procedures Samples may be categorized broadly into four heads, namely : (a) Gross Sample : A sample that represents the whole lot and may vary from a few grams or less to several pounds based on the nature of the bulk material. For Solids Sampling of solid materials are comparatively more difficult than other materials because of the follow- ing three reasons, namely : (a) Variation in particle size. Sampling of solids can be best accomplished by adopting the following procedures : • To take 1/50 to 1/100th of the total bulk for gross samples. For Liquids Sampling of liquids may be carried out by following these procedures : • Small heterogenous liquid samples are first shaken thoroughly and then followed by immediate sampling. However, the latter method is preferred for obvious reasons since the analysis shall have a better hold on the accuracy and precision of the analysis. A few specific examples are stated below : (a) A 24 hour urine sample collections are usually more reliable than single specimens. For example : (a) A breathe sample may be collected by allowing the subject to blow into an evacuated bag. Errors The famous adage—‘to err is human to forgive divine’—literally means that it is natural for people to make mistakes. However, errors in analytical chemistry or more precisely in pharmaceutical drug analysis are normally of three types, namely : (a) Determinate Errors (b) Instrumental Errors (c) Personal Errors These above mentioned errors would be discussed briefly here with specific examples. It is pertinent to mention here that errors outside the range of ‘permissible errors’ in the analyses of pharmaceutical substances may cause serious problems because most of these substances are usually highly toxic, potent and used exten- sively in life-saving processes across the globe. Determinate Errors Errors caused due to either incorrect adoption of an assay method or an incorrect graduation read out by an analyst are termed as determinate errors. In usual practice the determinate errors are subtle in nature and hence, not easily detected. A few typical examples of determinate errors are stated below : (a) Gravimetric Analysis : Where a compound is precipitated from a solution and the analyst believes that the analyte has been removed from the solution completely. Actually a small portion of the substance under investigation shall remain in solution. It may require an excess quantity of reagent to affect the colour change which ultimately shows completion of the chemical reaction between reagent and analyte. Therefore, in all such analytical procedures a ‘blank titration’ is performed simultaneously to determine how much reagent is required to affect the colour change when no analyte is present. Instrumnetal Errors The past three decades have witnessed a quantum progress and advancement in the field of analytical chemistry. Nowadays, both microprocessor based and computer-aided analytical instruments have more or less replaced the manually operated ones in any reasonably good analytical laboratory. One of the most prevalent determinate errors is caused by analytical intruments which are found to be ‘out of calibration’. Hence, it is very essential that such instruments need to be calibrated periodically, for instance, a pH meter is calibrated using a buffer solution of known pH, say adjusting the meter to read pH = 7.

Digoxin is significantly associated with cardiac muscle tissue effective bupropion 150 mg, as demonstrated by a 70:1 cardiac muscle to plasma digoxin concentration 2 ratio discount bupropion 150mg amex, which explains why its volume of distribution exceeds any normal physiologic space buy bupropion 150 mg overnight delivery. When these drugs are administered concomitantly, the tissue binding of digoxin is reduced. This is also an example of displacement but, in this case, quinidine has a higher affinity for the tissue protein binding site and displaces digoxin, resulting in a high unbound fraction in the tissue. What are the consequences of digoxin having a higher unbound fraction in the tissue due to quinidine displacement? We next consider the effect of a disease state (chronic renal failure) on the volume of distribution of phenytoin and digoxin. The equation below predicts that an increase in the unbound fraction in the plasma would result in an increase in the volume of distribution of phenytoin, which would increase the concentration of the active unbound phenytoin able to cross the blood-brain barrier. Because digoxin is negligibly bound to plasma proteins, changes in its concentration should not be of clinical significance. However, renal failure does reduce the cardiac muscle-to-plasma digoxin concentration ratio to 30:1. The mechanism by which renal failure alters the tissue protein binding of digoxin is presently not fully understood. The equation below predicts that an increase in the unbound fraction in the tissue would result in a decrease in the volume of distribution of digoxin and may cause an increased plasma digoxin drug concentration: In all these examples, the volume of distribution of the drug in question was altered as a consequence of a drug-drug or drug-disease state interaction. Drugs are generally less well distributed to highly perfused tissues (compared with poorly perfused tissues). Estimate the volume of distribution for a drug when the volume of plasma and tissue are 5 and 20 L, respectively, and the fraction of drug unbound in plasma and tissue are both 0. The portion of drug that is not bound to plasma protein is pharmacologically active. Penetration of drug into tissues is directly related to the extent bound to plasma proteins. Predict how the volume of distribution (V) would change if the phenytoin unbound fraction in plasma decreased from 90% to 85%. Assume that unbound fraction in tissues (Ft) and volumes of plasma (Vp) and tissues (Vt) are unchanged. A new drug has a tissue volume (Vt) of 15 L, an unbound fraction in plasma (Fp) of 5%, and an unbound fraction in tissues (Ft) of 5%. What will be the resulting volume of distribution if the plasma volume (Vp) is reduced from 5 to 4 L? How is the volume of distribution (V) of digoxin likely to change if a patient has been taking both digoxin and quinidine and the quinidine is discontinued? Assume that plasma volume (Vp), tissue volume (Vt), and unbound fraction of drug in plasma (Fp) are unchanged. Solve the equation using Vp = 5 L, then re-solve using 4 L and compare: If Vp is decreased to 4 L, 8-11. Remember, when quinidine is administered concomitantly with digoxin, quinidine competes with digoxin for tissue binding sites and increases the unbound fraction of digoxin in the tissues (Ft). Therefore, assuming Vp and Vt remain unchanged, the effect of quinidine is shown below: When quinidine is discontinued, the unbound fraction of digoxin in the tissues (Ft) decreases as the tissue binding sites formerly occupied by quinidine become available. Draw representative concentration versus time curves for: (a) a drug that diffuses into highly vascularized tissue before equilibrating in all body compartments, and (b) a drug that distributes equally well into all body compartments. Clinically, what type of loading dose adjustments can be made to account for these factors? A patient has a total plasma phenytoin concentration of 19 mcg/mL with a serum albumin concentration of only 2. In the same patient as described in discussion point D-4, calculate a new total phenytoin concentration that would yield a therapeutic unbound phenytoin concentration. Describe the impact of disease and altered physiologic states on the clearance and dosing of drugs. Define the methods of hepatic drug metabolism and the approaches used to quantitate and characterize this metabolism. Define both the physiologic and mathematical relationship of drug clearance to glomerular filtration. Although both organs share metabolic and excretory functions, the liver is principally responsible for metabolism and the kidneys for elimination. The importance of these organs cannot be overestimated in determining the magnitude and frequency of drug dosing. Additionally, an appreciation of the anatomy and physiology of these organs will provide insight into the impact of disease and altered physiologic states, as well as concomitant drug administration, on the clearance and dosing of drugs. The physical and chemical properties of a drug are important in determining drug disposition. For example, lipophilic drugs (compared with hydrophilic drugs) tend to be: • bound to a greater extent to plasma proteins, • distributed to a greater extent throughout the body, and • metabolized to a greater extent in the liver.

The negative slope of the residual line is referred to as alpha (α) buy discount bupropion 150mg on line, and α is the distribution rate constant for the two-compartment system order bupropion 150 mg mastercard. A dose of drug is administered by rapid intravenous injection buy cheap bupropion 150 mg line, and the concentrations shown in Table 6-1 result. The last four points form a straight line, (similar to Figure 6-5) so back-extrapolate a line that connects them to the y-axis. Then, for the first five points, extrapolated values can be estimated at each time (0. Subtracting the extrapolated values from the actual plasma concentrations yields a new set of residual concentration points, similar to those values shown in Table 6-2. Plot the residual concentrations (on the same semilog paper) versus time and draw a straight line connecting all of your new points (similar to Figure 6-7). Note that α must be greater than β, indicating that drug removal from plasma by distribution into tissues proceeds at a greater rate than does drug removal from plasma by eliminating organs (e. Plasma drug concentrations with a two-compartment model after an intravenous bolus dose. For a one-compartment model (Figure 6-8), we know that the plasma concentration (C) at any time (t) can be described by: -Kt Ct = C0e (See Equation 3-2. The equation is called a monoexponential equation because the line is described by one exponent. The two-compartment model (Figure 6-9) is the sum of two linear components, representing distribution and elimination (Figure 6-10), so we can determine drug concentration (C) at any time (t) by adding those two components. Therefore: -αt -βt Ct = Ae + Be This equation is called a biexponential equation because two exponents are incorporated. For the two-compartment model, different volume of distribution parameters exist: the central compartment volume (Vc), the volume by area (Varea, also known as Vβ), and the steady-state volume of distribution (Vss). As in the one-compartment model, a volume can be calculated by: For the two-compartment model, this volume would be equivalent to the volume of the central compartment (Vc). The Vc relates the amount of drug in the central compartment to the concentration in the central compartment. If another volume (Varea or Vβ) is determined from the area under the plasma concentration versus time curve and the terminal elimination rate constant (β), this volume is related as follows: This calculation is affected by changes in clearance (Cl). The Varea relates the amount of drug in the body to the concentration of drug in plasma in the post-absorption and post-distribution phase. Although it is not affected by changes in drug elimination or clearance, it is more difficult to calculate. One way to estimate Vss is to use the two-compartment microconstants: or it may be estimated by: using A, B, α, and β. Because different methods can be used to calculate the various volumes of distribution of a two- compartment model, you should always specify the method used. When reading a pharmacokinetic study, pay particular attention to the method for calculating the volume of distribution. Clinical Correlate Here is an example of one potential problem when dealing with drugs exhibiting biexponential elimination. Recall that A steeper slope equals a faster rate of elimination resulting in a shorter half-life. If a terminal half-life is being calculated for drugs such as vancomycin, you must be sure that the distribution phase is completed (approximately 3-4 hours after the dose) before drawing plasma levels. Plasma drug concentrations with a one-compartment model after an intravenous bolus dose (first-order elimination). Plasma drug concentrations with a two-compartment model after an intravenous bolus dose (first-order elimination). The plasma drug concentration versus time curve for a two- compartment model is represented by what type of curve? For a two-compartment model, which of the following is the term for the residual y-intercept for the terminal portion of the natural- log plasma-concentration versus time line? The equation describing elimination after an intravenous bolus dose of a drug characterized by a two-compartment model requires two exponential terms. A patient is given a 500-mg dose of drug by intravenous injection and the following plasma concentrations result. K12 represents the rate constant for drug transfer from compartment 1 (central) to compartment 2 (peripheral). The y-intercept associated with the residual portion of the curve (which has a slope of -α) is A. One for distribution phase and the other for elimination or post- distribution phase. Describe situations for which it would be better to use a two-compartment model rather than a one-compartment model. What is the minimum number of plasma-concentration data points needed to calculate parameters for a two-compartment model?

The chemist carefully removes the stopper from the bottle buy bupropion 150mg overnight delivery, wearing eye protection safe bupropion 150 mg. The reaction mixture is now poured onto about 500 grams of crushed ice in a 1000 or 2000 ml beaker generic bupropion 150 mg otc. Once the ice has melted, the red layer of product is separated, and the water is extracted with about l00 ml of petroleum ether or regular ethyl ether. The ether extract is added to the product, and the combined product is washed first with water, and then with a solution of sodium carbonate in water. One can be sure that all the acid is removed from the product when some fresh carbonate solution does not fizz in contact with the product. This is important because if the ether were allowed to remain in it, too much pressure would be generated in the next stage inside of the bomb. Also, it would interfere with the formation of a solution between the product and methylamine or ammonia. It is not necessary to distill the product because with a yield of over 90%, the crude product is pure enough to feed into the next stage. To remove the ether from the product, the crude product is poured into a flask, and a vacuum is applied to it. Next, isopropyl alcohol is added with stirring until a nice smooth solution is formed. It is not good to add too much alcohol because a more dilute solution reacts slower. This temperature is maintained for about 3 hours or so, then it is allowed to cool. Once the pipe is merely warm, it is cooled down some more in ice, and the cap unscrewed. The reaction mixture is poured into a distilling flask, the glass- ware rigged for simple distillation, and the isopropyl alcohol and excess ammonia or methylamine is distilled off. When this is done, the residue inside the flask is made acid with hydrochloric acid. It contains close to 20 grams of bromo compound which may be used again in later batches. The toluene is combined with the free base layer, and the toluene is distilled off. Inhalants Our understanding is that there is no such thing as safe use of inhalants; their psychoactive effects are inseparable from nerve and organ damage. The including of this chapter to the “drug recipes” does not imply that inhalants are anything but dangerous. Take your substance of choice, open a plastic bag and pour a small amount of the fluid into the bag. Now, put the bag up to your mouth and breath into the bag, filling it with your breath, then inhale - you will be inhaling the psychoactive fumes, hence you will get high. You only need a gas can, or container with a pour spout and your substance (inhalant) of choice. You simply fill the bottom of the gasoline can with the fluid, place your mouth around the pour spout, and inhale the psychoactive fumes. You take the substance of your choice, usually hold the can upright, push the top in to discharge the gas (inhalant) place your mouth over the top and inhale the gas being projected from the can. Spray the paint on the piece of cloth, fold the cloth in half and breath through the clean side. By doing this - as you inhale your breath will act as a vacuum, and carry the fumes from the paint through the cloth into your lungs. You will usually fell very disoriented, almost as if you are very drunk, allot of people will here all sorts of sounds (usually ringing in the ears)... Then add 30ml of it to the codeine/water mix and then add 50ml of chloroform and shake and allow the heavier solvent to sink to the bottom. Then you must separate off the chloroform layer by using a siphon (use an eyedropper if you need to), then wash the remanding solution again with 30ml of chloroform and once again remove it. All of the water must be out, and you can pipette it or use a separator of some kind (like a flask with a tap, so you shut it off when the water gets close to running through). Just have a plate sitting on top of the pot and slowly tip in solution and watch white crystalline codeine base appear as the chloroform reduces out by dryness. Then when melted, place in the codeine and it all must dissolve and be able to swish around. It will turn different colors and it will be hard to tell when it’s cooked, but let it take about 5 minutes or when the temperature hits around 230 Celsius and then it will be done, and it will stick to the sides of the tube when ready. Then tip some water back into the now cooler test-tube and rinse all of it out into the beaker. Next add caustic solution drop by drop till you get to pH 14 (take about 3ml of the solution stated above).