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Suboxone (sublingual film) was approved in 2010; the tablet (sublingual) form was approved in 2002 and was voluntarily withdrawn from the market by Reckitt Benckiser in Sept. Bisschops (Tarpon Biosystems): This statement is absolutely true for applications that involve capture of the product and/or some high resolution polishing steps. For flow-through applications (or negative chromatography), membrane adsorbers have already paved the way for disposable chromatography. One of the most important reasons why chromatography has not been available in a disposable format is caused by the nature of the chromatography process itself: it is essentially a mass driven process, where the size of the column is governed by the amount of product that needs to be bound. For membrane processes and other flow- Disposable through applications, the most important system dimensions are determined by the volume that needs to be processed. Chromatography As a result, the successful introduction of disposable bioprocessing has largely Moderated by Amy Ritter been enabled by the process intensification that resulted from the increases in expres- sion levels over the past decade. In essence, this has allowed us to produce the same amount of product with much less water articipating in the roundtable are Eric and hence with a significantly reduced Disposables have Grund, PhD, senior director of bio- volume. This hampers the translation of batch-wise chromatographic processes processing has lagged Barriers to implemetation into a single-use or disposable application, behind that for PharmTech: Chromatography has been unless one uses a technology that would one of the last components of the biopro- allow one to use the media over so many other applications. What are the constraints of the chromatog- Thompson (Polybatics): Columns PharmTech spoke raphy process that have proved challenging are very expensive systems, and the cost with industry experts to implement in single-use format? Also, the cost tal barrier based on a narrow view of the of buying the resins themselves are fairly of implementing pros and cons. Protein disposable often very tolerant to cleaning and with- A has been on patent until around March stand re-use, so it’s tough to throw them 2010, so there’s been a monopoly on that chromatograpy away after single-use, especially if tests particular ligand, which has maintained a show they still perform well after many very high price of the resin. The benefits of speed, facility flex- two factors have been a real impediment 48 Pharmaceutical Technology OctOber 2012 PharmTech. And there hasn’t been anyone out ferent sensors deployed and the operating and then, can you make a single-use media there who has come up with a format that range and accuracy required of those sen- or functional element to go into that. You pump a and storage between times and so are not What users are doing is making the media slurry into the column, and have to let it seen as single-use per se. What you’re seeing today is compa- No one has come up with a format that is nies offering the easy part, the containment part, of the disposable chromatography, the truly comparable to traditional packed- column shells, and packing them. The dif- ficult part of the technology is finding new bed chromatography in terms of its ability ways to stretch the economics of running longer, running smaller batches, cycling the to purify and capture the target. If it doesn’t settle quite right, you can Tingley (Repligen): If we take a look at PharmTech: A few disposable chromatog- get voids in the column, and you have to the process as a whole, and we look at the raphy platforms are currently available, in- pack again. There’s a lot of art in packing adoption curve of single-use technologies, cluding packed-bed, simulated moving bed the column to get it to perform right. Until recently, there haven’t get to an economical cost point than the tion, when binding capacity and resolving been those kinds of plug-and-play systems. Conventionally, the Mann (Merck Millipore): Chroma- functional technologies would be replac- first step in downstream purification is tography processes, while not fully single- ing stainless-steel pipework with plastic product capture, in bind/elute mode, and use, have been operating in a hybrid way tubing, or replacing stainless-steel tanks a packed bed is needed to achieve the objec- for some time with the implementation with plastic bags. Frequently, a small num- tanks and replacement with single-use or microfiltration, these are examples of ber of cycles is used to handle large volumes bags is, together with the use of single-use functional technologies, which have to be of feed. Making functional technology ing a continuous processing approach with savings when comparing single-use to tra- costs money, and functional technologies several small columns cycled in sequence. This helps ad- Constraints of the chromatography multimode resins which are also reason- dress the cost equation because the resin process that make it difficult to imple- ably expensive. So, ducible performance and avoid multiple tiple buffer inlets, column flow reversal there are two parts of the problem: can you column-packing in the production work- and bypass and fraction outlet. The Arc sensor head enables the ﬁrst fully integrated intelligent sensors that do not rely on a transmitter. Arc can be integrated into existing 4-20 mA or digital environments to improve signal quality and data efﬁciency. Calibration statistics, usage history, and diagnostics are stored in the sensor for quality management and troubleshooting. Visit us at BioProcess For more information on how the Arc International can improve your process analysis, Oct. As a result, this technol- rification, it has not found adoption in valves and sophisticated control to assure ogy can make prepacked disposable chro- protein separations primarily due to the accurate column switching without cross matography a viable alternative, especially greater complexity of the flowpath and contamination. Disposable valving is the missing link coming onto the market may address that The further downstream you are in your in providing economically viable, fully aspect, but the added complexity of op- process, the fewer the impurities. When disposable downstream processing for eration compared to conventional batch there are only small amounts remaining, bind/elute applications. Another feature chromatography will likely continue to membrane chromatography is attractive of continuous chromatography is that it be a hurdle to adoption. Single-use nuity eliminates or significantly reduces prepacked columns and coupled to the components are often preferred for scav- interstage product hold steps and allows fact that the resin is cycled more times per enging, especially because cleaning may be multiple unit operations to be operated batch. Thus, the time in facility cal-scale batches where, conventionally, the resin may be thrown away after only a few batches and so is nowhere near its end of If the product is a monoclonal antibody, life point. Multicolumn approaches enable then likely there is a template already in better resin utilization, getting closer to the lifetime of the resin and thus saving cost. Although single-use For producing tons of product, the col- can be shortened by a factor of two, which implementation shows clear cost benefits umn volumes are large, several hundred in many cases translates into a significant at the smaller pilot/clinical scale manufac- or even thousands of liters, and at this size, increase in facility throughput. In general, Mann (Merck Millipore): Probably, the steel installation can be more cost-effective. For instance, if the product is a Tingley (Repligen): In stepping back a more flexibility in manufacturing and in monoclonal antibody, then likely there is little bit, you can ask—why do people want a shorter change-over time. These features a template already in place for purifica- to adopt single-use technologies? I don’t are particularly important for multiprod- tion, typically protein A affinity chroma- think the answer has changed as we’ve uct facilities such as clinical manufacturing tography, followed by cation exchange changed the technologies—it’s speed— facilities and contract manufacturing or- bind-elute and then anion exchange flow getting through the process quicker, being ganizations. Both the protein A affinity and able to develop multiproduct facilities, the advantage of disposable bioprocess- cation exchange are almost certainly going being able to put more molecules through ing technologies is more obvious than for to be conventional packed-bed columns. Although traditionally the anion exchange the reason why the disposable trend has Prepacked chromatography columns fit was also a packed-bed column, anion ex- developed and has been so successful over very well in streamlining the workflow in change flow through membrane adsorbers the past 15 or 20 years. At consider them as a single-use or disposable Membrane adsorbers are also finding one end of the continuum are users who product for other applications than clini- application elsewhere when used in flow really want to use chromatography col- cal manufacturing. While single-use membrane ad- sive, in terms of the overall operation, they sunk capital in legacy facilities. Users operate on We do see, however, a growing trend flow through applications, the relatively a continuum, and you see systems ranging in even existing legacy facilities moving lower capacity compared with resins lim- from pure disposables to hybrid facilities.
Precautons Hepatc impairment (Appendix 7a); renal impairment; alcohol dependence; lactaton (Appendix 7b); pregnancy (Appendix 7c); overdosage: chapter 7 purchase roxithromycin with visa antibiotic without penicillin. Adverse Efects Rare but rashes and blood disorders reported; important: liver damage (and less frequently renal damage) following overdosage; dyspepsia buy roxithromycin 150 mg free shipping antibiotic justification form. In additon to pain relief it confers a state of euphoria and mental detachment; repeated administraton may cause dependence and tolerance purchase generic roxithromycin antimicrobial hand wash, but this should not be a deterrent in the control of pain in terminal illness. Regular use may also be appropriate for certain cases of non-malignant pain, but specialist supervision is required. In normal doses common adverse efects include nausea, vomitng, constpaton and drowsiness; larger doses produce respiratory depression and hypotension. Codeine is an opioid analgesic much less potent than morphine and much less liable, in normal doses, to produce adverse efects including dependency. Contraindicatons Respiratory depression; obstructve airways disease; acute asthma atack; where risk of paralytc ileus; hypersensitvity; head injury; increased intracranial pressure. Precautons Hepatc impairment (Appendix 7a) and renal impairment; opioids dependence; lactaton; overdosage: chapter 7. Elderly or frail- Acute pain: 5 mg, adjust according to response (not suitable for patents having oedema). Afer 1 to 6 months: initally 100 to 200 µg/ kg every 6 h, 2 to 12 years: initally 200 µg/ kg every 4 h, 12 to 18 years: initally 2. Myocardial infarcton: 10 mg (2 mg/min), followed by another 5 to 10 mg if necessary. Oral or subcutaneous or intramuscular injecton Chronic acute pain: 5 to 20 mg every 4 h or as per recovery (not suitable for patent having oedema). Precautons Renal and hepatc impairment (Appendix 7a); reduce dose or avoid in elderly and debilitated; dependence (severe withdrawal symptoms if withdrawn abruptly); hypothyroidism; convulsive disorders, seizure disorder; decreased respiratory reserve and acute asthma; hypotension; prostatc hypertrophy; pregnancy (Appendix 7c) and lactaton (Appendix 7b); overdosage: chapter 7. Adverse Efects Nausea, vomitng (partcularly in inital stages) constpaton, drowsiness, also dry mouth, anorexia; spasm of urinary and biliary tract; bradycardia/tachycardia; palpitatons; decreased libido; rash, urtcaria, pruritus; sweatng; headache; facial fushing; vertgo; postural hypotension; hypothermia; hallucinatons, euphoria, confusion, dependence; miosis; larger doses produce respiratory depression and hypotension; somnolence; sepsis, peripheral oedema. Pentazocine Pregnancy Category-C Indicatons Moderate to severe pain; pre-anaesthetc medicaton; colic; trauma; surgical procedures; burns. Dose Oral Adult- Pentazocine 50 mg every 3 to 4 h preferably afer food (range 25 to 100 mg, max. Contraindicatons Patents dependent on opioids; arterial or pulmonary hypertension; heart failure; narcotc dependence; hypersensitvity; ischaemia; myocardial infarcton. Precautons Avoid in porphyria; interactons (Appendix 6a); impaired respiratory functon; pregnancy (Appendix 7c); renal or hepatc functon; thyroid dysfuncton; biliary tract impairment. Dose Adult- Moderate to severe pain: 50 to 100 mg, 4 to 6 hourly (max 400 mg/day). Contraindicatons Patents with suicidal tendency; raised intracranial pressure; severe renal impairment; acute alcoholism; lactaton. Precautons Renal or hepatc impairment; history of epilepsy; infammatory or obstructve bowel disease; myasthenia gravis; hypothyroidism; adreno-cortcal insufciency; respiratory depression; prostatc hyperplasia; pregnancy (Appendix 7c). Antacids and Antulcer Drugs Antacids (usually containing aluminium or magnesium compounds) can ofen relieve symptoms in ulcer dyspepsia and in non-erosive gastro-oesophageal refux; they are also some- tmes used in non-ulcer dyspepsia but the evidence of beneft is uncertain. Antacids are best given when symptoms occur or are expected, usually between meals and at bedtme, Liquid preparatons are more efectve than solids. Aluminium-and magnesium-containing antacids (for example aluminium hydroxide and magnesium hydroxide), being relatvely insoluble in water, are long-actng if retained in the stomach. Magnesium-containing antacids have a laxatve efect whereas aluminium-containing antacids may be const- patng. H2-receptor antagonists heal gastric and duodenal ulcers by reducing the secreton of gastric acid as a result of histamine H2-receptor blockade; they can also relieve gastro-oesophageal refux disease. High doses of H2-receptor antagonists have been used in the Zollinger-Ellison syndrome, but a proton-pump inhibitor is now preferred. Maintenance treatment with low doses has largely been replaced in Helicobacter pylori positve patents by eradicaton regimens. Maintenance treatment may occasionally be used for those with frequent severe recurrences and for the elderly who sufer ulcer complicatons. Treatment of undiagnosed dyspepsia with H2-receptor antago- nists may be acceptable in younger patents but care is required in older patents because their symptoms may be caused by gastric cancer. Treatment also reduces the risk of acid aspiraton in obstetric patents at delivery (Mendelson syndrome). General and inex- pensive measures like introducing healthy life-style, stopping smoking and taking antacids should be promoted. The possi- bility of malignant disease should be considered in all patents over the age of 40 years who are suspected of having an ulcer. Gastric and duodenal ulcers are healed by 4-8 weeks treat- ment with H2-receptor antagonists but there is a high rate of relapse (greater than 70% over 2 years) requiring mainte- nance therapy. This is undoubtedly cost-efectve compared to the alternatves of long-term maintenance therapy with low-dose H2-receptor antagonists or repeated treatment of recurrent ulcers. Eradicaton regimens are based on a combinaton of an acid-reducing (‘antsecretory’) drug and antbiotcs. The following model eradicaton regimen is suggested on the basis of its efcacy and simplicity (only doses suitable for adults are shown): • Omeprazole 40 mg daily for 1 week plus • Metronidazole 400 mg thrice daily for 1 week plus • Amoxycillin 500 mg thrice daily for 1 week The decision on choosing an eradicaton regimen should take into account local resistance to antbacterials, cost and avail- ability of the necessary drugs. A proton- pump inhibitor such as omeprazole is more efectve but it is also more expensive. It can occur with gastric and duodenal ulceraton and gastric cancer but most commonly it is of uncertain origin. Patents with non-ulcer dyspepsia should be advised to avoid smoking, alcohol and aggravatng foods and to eat small regular meals to aid digeston. Non-ulcer dyspepsia tends to be self-limitng but antacids and H2-receptor antagonists are ofen used to suppress gastric acid. Efectve treatment is important in the presence of severe oesophageal ulceraton to prevent longer term complicatons such as oesophageal stricture and carcinoma. Inital treatment is guided by the severity of symptoms and treatment is then adjusted according to response. H2-receptor antagonists suppress acid secreton and they may relieve symptoms and permit reduc- ton in antacid consumpton. Zollinger-Ellison Syndrome Management of Zollinger-Ellison syndrome requires high dose H2-receptor antagonist treatment. The proton pump inhibitors are more efectve partcularly for cases resistant to other treatment but they are more expensive. Contraindicatons Hypophosphataemia; undiagnosed gastroin- testnal or rectal bleeding; appendicits; por- phyria; hypersensitvity to aluminium salts. Precautons Impaired renal functon and renal dialysis; hepatc impairment (Appendix 7a); constpaton; dehydraton; fuid restricton; gastrointestnal disorders associated with decreased bowel motlity or obstructon; pregnancy (Appendix 7c); interactons (Appendix 6c); oedema, cirrhosis and low sodium diets.
Formulations of Semisolid Drugs 245 Tretinoin Gel Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 0 purchase roxithromycin without prescription bacteria cells. Prepare suspension of items 6 and 7 and add solution of items 8 and 9 to the well-stirred suspension buy generic roxithromycin on line virus your computer has been blocked department of justice. This formulation uses patented methy meth- hol cheap roxithromycin 150mg free shipping antibiotic mastitis, trolamine, and butylated hydroxytoluene. Chemically, acrylate/glycol dimethacrylate crosspolymer porous tretinoin is all-trans-retinoic acid, also known as (all- microspheres (Microsponge System®) to enable inclusion E)3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)- of the active ingredient, tretinoin, in an aqueous gel. Triacontanol Ointment Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 0. The other ingredients are dissolved in the puri- ﬁed water and are also warmed to about 75°C. All ingredients are then mixed together and melted on a steam bath and warmed to about 75°C. Tridax Procumbens Ointment Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 5. Tridax procumbens leaf extract is dispersed in pure propylene glycol along with propylpara- 1. Carbopol 934 is dispersed in a propy- water (1 L) for 72 hours at room temperature. Water is decanted and then concentrated to 100 with methylparaben in another vessel. Formulations of Semisolid Drugs 247 Trolamine Salicylate Cream Bill of Materials Scale (mg/tablet) Item Material Name Quantity/kg (g) 50. Add items 1–7 and mix well at 80°–85°C; con- tinue mixing; while cooling to 65°C, add items Ultrasonic Adhesive Gel Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 5. Prepare solution of item 1 in item 2 by heating to 70°C, and add item 3 slowly to obtain a homogeneous suspension. Dissolve butylhydroxytoluene in the warm vita- min A, add cremophor, and mix with the molten Lutrol E grades. Vitamin A Ointment Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 2. Sift in 4 g hydroxypropyl cellulose slowly over approximately 15 minutes while blending to 1. Formulations of Semisolid Drugs 249 Vitamin C Vaginal Ointment Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 12. Vitamin E Gel-Cream Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 100. Charge item 12 (two thirds) to Becomix, heat items 9 and 1 in a separate vessel; mix using a to 80°–85°C, and transfer to a stainless steel stirrer, then cool down to 40°–45°C. Charge in a melting vessel items 2–7, one at a pass dispersion twice through a homogenizer. Formulations of Semisolid Drugs 251 Zinc Oxide Lotion Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 7. Zinc Oxide Ointment Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 120. Its inactive ingredients eral oil, propylparaben, puriﬁed water, sodium borate, and are aloe vera gel, balsan (specially puriﬁed balsam peru), tocopheryl (vitamin E acetate). Zinc Pyrithione Detergent Lotion Bill of Materials Scale (mg/g) Item Material Name Quantity/1000 Tablets (g) 547. Zinc Undecylenate Cream Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 7. Heat items 6–10 separately to 70°–75°C and add to the above mixture, mixing while cooling; 1. Formulations of Semisolid Drugs 253 Zirconium Oxide Lotion Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 15. Dry blend items 1 and 2 and add them to water slowly while agitating with maximum shear until smooth. Te programme was subsequently expanded to include evaluations of carcinogenic risks associated with exposures to complex mixtures, lifestyle factors and biological and physical agents, as well as those in specifc occupations. Te objective of the programme is to elaborate and publish in the form of monographs critical reviews of data on carcinogenicity for agents to which humans are known to be exposed and on specifc exposure situations; to evaluate these data in terms of human risk with the help of international working groups of experts in carcinogenesis and related felds; and to indicate where additional research eforts are needed. Support has also been provided since 1992 by the United States National Institute of Environmental Health Sciences, Department of Health and Human Services. Te contents of this volume are solely the responsibility of the Working Group and do not necessarily represent the ofcial views of the United States National Cancer Institute, the United States National Institute of Environmental Health Sciences, the United States Department of Health and Human Services, or the European Commission. Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. Te designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Te mention of specifc companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. Te Monographs evaluate cancer hazards, despite the historical presence of the word ‘risks’ in the title. Inclusion of an agent in the Monographs does not imply that it is a carcinogen, only that the published data have been examined. Equally, the fact that an agent has not yet been evaluated in a Monograph does not mean that it is not carcinogenic. Similarly, identifcation of cancer sites with sufcient evidence or limited evidence in humans should not be viewed as precluding the possibility that an agent may cause cancer at other sites. Te evaluations of carcinogenic risk are made by international working groups of independent scientists and are qualitative in nature. Although every efort is made to prepare the Monographs as accurately as possible, mistakes may occur. Biggar Auckland Cancer Society Research Centre Queensland University of Technology University of Auckland Brisbane Auckland Australia New Zealand Esperanza J. Invited Specialists do not serve as Meeting Chair or Subgroup Chair, draf text that pertains to the description or interpretation of cancer data, or participate in the evaluations. Each participant was asked to disclose pertinent research, employment, and fnancial interests. Current fnancial interests and research and employment interests during the past 4 years or anticipated in the future are identifed here. All grants that support the expert’s research or position and all consulting or speaking on behalf of an interested party on matters before a court or government agency are listed as signifcant pertinent interests. Guyton London Béatrice Lauby-Secretan (Rapporteur England Exposure Data) Ho-Sun Lee Dana Loomis (Rapporteur Cancer in Humans) 7 Olaf Kelber Heidi Mattock (Scientifc Editor) World Self-Medication Industry Douglas Puricelli Perin Steigerwald Arzneimittelwerk GmbH Mónica S. Sierra Darmstadt Kurt Straif (Head of Programme) Germany Jiri Zavadil 8 Administrative Assistance Egon Koch World Self-Medication Industry Sandrine Egraz Dr. He holds stock of pharmaceutical companies marketing drugs that are reviewed at this meeting. He provides expert testimony with respect to the commercialization of Ginkgo biloba extracts.
Therefore buy roxithromycin with amex infection 6 months after hysterectomy, it may be inferred that—‘in a saturated solution of a difficultly soluble salt buy genuine roxithromycin online virus protection, the product of the molecular concentration of its ions is constant’ buy roxithromycin with a mastercard antibiotic nail. Now, if to the resulting supernatant liquid, which is nothing but a saturated solution of barium sul- phate, an additional small quantity of either a soluble barium salt or a soluble sulphate is provided, a slight further precipitation may occur. Evidently, this decrease in the concentration of the ions in either instance may be achieved by the combination of barium and sulphate ions to give rise to the insoluble barium sulphate thereby forcing the reaction towards completion. In short, the common-ion effect is employed invariably in carrying out the gravimetric analysis of pharmaceutical substances so as to drive reactions toward completion. The gravimetric meth- ods adopted vary according to the nature of the substance under determination. However, most of the sub- stances being estimated gravimetrically fall into one or the other categories stated below, which would be discussed briefly with suitable examples : (a) Substances assayed gravimetrically, (b) Substances assayed after conversion : (i) Substances assayed after conversion to Free Acid, (ii) Substances assayed after conversion to Free Base, (iii) Substances assayed after conversion to Free Compound, and (iv) Substances assayed after conversion to Derivatives or Substitution Products. A few typical examples are cited below so as to expatiate the procedure as well as the theoretical aspects. Theory : The following reaction forms the basis for the calculation of the theoretical amount of silver nitrate solution required as well as the purity of the given sample of NaCl. From above, the percentage purity of the given sample of NaCl may be found as shown below : 58 44. Consequently, the percentage purity of the sample is determined by the formula : W E 100 = % S where, W = Wt. By incorporating the data given above, the amount of sodium chloride present in 100 g of the sample i. Check and confirm that the resulting solution is acidic with the help of blue litmus paper. The requisite quantity of silver nitrate solution must be added in small lots at intervals with constant stirring with a glass rod. Cover the beaker with a watch-glass and boil the contents very gently with occasional stirring (to avoid bumping of the liquid and loss of volume). Stop heating and digest the mixture for 10 minutes so as to agglomerate the precipitate and enhance settling thereby leaving a clear supernatant liquid. Add 2 drops of silver nitrate solution to the hot supernatant liquid in order to confirm whether precipitation is completed. Take a properly prepared Gooch crucible, heat to constant weight and fit it into the suction flask. Decant most of the supernatant liquid first into the Gooch crucible by applying gentle suction to hasten filtration. Wash the precipitate on the Gooch crucible at least thrice with 15 ml portions of 0. Now, apply vigorous suction to drain out the liquid from the precipitate to the maximum extent. Dry the crucible to a constant weight between 110-120°C in an electric oven until two concurrent weighings are achieved. Thus, the weight of the crucible (tare) must be deducted from the weight of the crucible plus the precipitate to arrive at the weight of silver chloride duly obtained from the sample. Add the requisite quantity of the oxine reagent and then add a 2 N solution of ammonium acetate gradually from a pipette till precipitation just commences. Add a further portion (50 ml) of ammonium acetate solution with vigorous stirring. Filter the precipitate through No : 3 or 4 sintered glass crucible that has been previously dried to a constant weight at 130—150°C. Cognate Assays A good deal of pharmaceutical substances are officially assayed gravimetrically as appears in Table 10. All these typical cases shall be discussed briefly with their appropriate examples in the following sections. Substances Assayed after Conversion to Free Acid A few official pharmaceutical substances may be assayed gravimetrically by affecting separation, purification, and weighing an organic medicinal compound without causing any permanent change in composition. It is an usual practice that before extraction of the organic medicinal compound, the sample of the crushed tablets is carefully washed with petroleum benzene to get rid of undesirable components, for instance : lubricants and binders that would be extracted along with the organic medicinal compound by such solvents as ether or chloroform which is employed subsequently. The resulting aqueous solution of the salt of the respective organic medicinal compound is subsequently made acidic and the liberated organic acid (amobarbital) is finally extracted with ether or chloroform. Add to it 5 ml of 2 M hydrochloric acid and extract with 50 ml of ether and then with successive 25 ml quantities of ether until complete extraction is affected. Add the ether to the main ethereal extract, evaporate to low bulk, add 2 ml of absolute ethanol, evaporate to dryness and dry the residue to constant weight at 105°C. Cognate Assays There are certain pharmaceutical substances that may be assayed after their conversion to the respec- tive free acids as shown in Table 10. Substances Assayed after Conversion to Free Base In a specific instance where the organic medicinal substance is basic in nature e. Papaverine Hydrochloride Tablets Materials Required : Sodium hydroxide (2 M) (dissolve 8. Add to it 15 ml of 2 M sodium hydroxide and extract with 50 ml of chloroform and then with successive 25 ml quantities of chloroform until complete extraction is affected. Add the chloroform to the main chloroform extract, evaporate to a small volume, add 2 ml of absolute ethanol, evaporate to dryness and dry the residue to constant weight at 105°C. Theory : Amodiaquine hydrochloride possesses two moles of inherent water of crystallization, and hence the precentage base is calculated with reference to the substance dried over P2O5 at a pressure not exceeding 5 mm of Hg. Usually, the assay is performed on one portion of the sample and the drying on a separate portion altogether. The underlying principle of the method is based upon the precipitation of amodiaquine base that is generated as a precipitate when the salt is decomposed in aqueous medium with dilute ammonia. Cognate Assays A few other pharmaceutical substances are also determined after conversion to free bases as recorded in Table : 10. Substances Assayed After Conversion to Free Compound In certain specific cases either the pure pharmaceutical substance or dosage forms are quantitatively converted to free compound. This conversion to free compound is quantitative and hence forms the basis of gravimetric analysis. A few typical examples belonging to this category are, namely : progesterone suspension sterile, progesterone tablets, sodium lauryl sulphate, mephobarbital tablets and sorbitan monooleate. Mephobarbital Tablets Materials Required : Mephobarbital : 300 mg ; hexane : 100 ml ; chloroform : 150 ml ; alcohol (95% v/v) : l0 ml. Transfer an accurately weighed portion of the powder equivalent to about 300 mg of mephobarbital to an extraction thimble. Extract with 15 ml of solvent hexane, allow the thimble to drain, transfer to a continuous extraction apparatus pro- vided with a tared flask, and extract the mephobarbital with chloroform for 2 hours. Evaporate the chloroform on a steam bath with the aid of a current of air, cool, dissolve the residue in about 10 ml of alcohol, evaporate, dry the residue at 105°C for 1 hour, cool and weigh. The weight of the residue represents the weight Cl3H14N2O3 in the portion of the tablets taken. Substances Assayed after Conversion to Derivatives or Substitution Products In pharmaceutical drug analysis a host of organic pharmaceutical substances are invariably converted quantitatively to their corresponding derivatives by virtue of interactions with certain functional entities, namely : aldehyde, ketone, amino, carboxyl, phenolic, hydroxyl etc.
When the method of administration of vitamin K was recorded buy roxithromycin paypal infection in stomach, it agreed with the stated routine method of administration in 92% of the 235 cases for which individual information could be found order roxithromycin with mastercard steroids and antibiotics for sinus infection. The relative risk for all childhood cancer associated with a hospital policy of intramuscular administration of vitamin K as compared with oral administration was 1 buy roxithromycin once a day antibiotic resistance legislation. There was a small increase in risk for all tumour types combined, due mainly to lymphoma in boys and neuroblastoma in boys and girls. The preparation was the same as that used in the United Kingdom (Draper & McNinch, 1994). In addition to the case–control study in northern England described above, Parker et al. As described above, information on hospital policy was obtained separately and independently by two people and then cross-validated. In units with a policy of selective prophylaxis, less than 30% of infants received intramuscular vitamin K at birth, while in units offering universal prophylaxis, sampling of case notes showed that more than 95% of babies received vitamin K. The risk for acute lymphoblastic leukaemia in children born in hospitals with a policy of universal prophylaxis relative to those born in hospitals with a policy of selective prophylaxis was 0. Information on hospital policy for neonatal vitamin K was obtained during the case–control studies of Passmore et. The observed numbers of cases in hospitals with universal and selective policies were compared with the numbers expected on the basis of national rates. Separate analyses were carried out for births in hospitals that followed one policy throughout the period of study and births in hospitals in which the policy changed during the period of study. The ratio tended to be smaller in hospitals with a selective policy than in those offering universal prophylaxis. Studies of Cancer in Experimental Animals No reports of studies specifically designed to investigate the carcinogenicity of vitamin K substances were available to the Working Group. One study on the initiating effects of menadione in an assay of liver foci in rats was available (Denda et al. Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanisms The studies summarized in this section should be considered in the light of the differences between naturally occurring forms of vitamin K that have a lipophilic side- chain at the 3-position of the 2-methyl-1,4-naphthoquinone (menadione) ring structure (phylloquinone and menaquinones) and the synthetic forms which lack this side-chain (menadione and its water-soluble derivatives). Lack of this side-chain results in profound differences in the absorption, tissue distribution and metabolism of natural K vitamins. In the strict sense, menadione is a provitamin K, because it is biologically active for the synthesis of vitamin K-dependent proteins only after conversion to the naturally occurring menaquinone-4 (four prenyl units) in vivo. It is absorbed chemically unchanged from the proximal intestine after solubilization into mixed micelles composed of bile salts and the products of pancreatic lipolysis. In healthy adults, the efficiency of absorption of phylloquinone in its free form is about 80% (Shearer et al. Within the intestinal mucosa, phylloquinone is incorporated into chylomicrons, is secreted into the lymph and enters the blood via the lacteals (Shearer et al. After a phylloquinone-containing meal, the plasma concentration peaks between 3 and 6 h (Shearer et al. Once in the circulation, phylloquinone is rapidly cleared at a rate consistent with its continuing association with chylomicrons and the chylomicron remnants that are produced by lipoprotein lipase hydrolysis at the surface of capillary endothelial cells. During the postprandial phase and after an overnight fast, more than half of the circulating phylloquinone is asso- ciated with triglyceride-rich lipoproteins, and the remainder is carried by low-density and high-density lipoproteins (Kohlmeier et al. Although phylloquinone is the major circulating form of vitamin K, menaquinone-7 is present in plasma at lower concentrations and has a similar lipoprotein distribution to phylloquinone. While phylloquinone in blood is derived exclusively from the diet, it is not known what proportion of circulating menaquinones such as menaquinone-7 derives from the diet or the intestinal flora (Shearer et al. A gradual slowing of the clearance rate was seen after the first 6 h (Shearer et al. This slowing of the clearance rate may be explained by the complexity of the plasma transport of phylloquinone, in which the proportion of phylloquinone associated with low-density and high-density lipo- proteins increases progressively (Lamon-Fava et al. The plasma disposition of oral doses of 5–60 mg phylloquinone (Konakion or AquaMephyton) is similar to that found after a more physiological dose (≤ 1 mg), with peak plasma concentrations at 4–6 h followed by a rapid clearance phase (Shearer et al. After an oral dose of 10 or 50 mg Konakion, the plasma concentration declined from the peak absorptive level at a similar log-linear rate as that seen after intravenous adminis- tration, with a terminal half-time of about 2 h for measurements up to 9–12 h (Park et al. The absorption of oral preparations of phylloquinone shows inter- and intra-individual variation and, for doses of Konakion ranging from 10 to 60 mg, the bioavailability was 10–63% (Park et al. The pharmacokinetics of phylloquinone after an intramuscular dose is completely different, showing sustained, slow release from the muscle site over many hours and marked inter-individual variation (Hagstrom et al. After intramuscular injection of phylloquinone (AquaMephyton R), most of the substance was carried by low-density and high- density lipoproteins instead of by triglyceride-rich (very-low-density) lipoproteins as found after oral administration (Hagstrom et al. An early study of the plasma disposition of 1 mg Konakion given orally or intra- muscularly at birth showed wide inter-individual differences during the first 24 h, especially after oral administration (McNinch et al. The peak plasma concen- tration after an oral dose occurred after 4 h; the median concentration was 73 ng/mL, which fell to 23 ng/mL after 24 h. The plasma concentration after administration of 1 mg of Konakion intramuscularly exceeded those after oral administration at all times, and after 24 h the median was 444 ng/mL. Physiologically, these concentrations compare with adult endogenous levels of about 0. By 24 days, the concentrations in both groups were mainly within the adult physiological range (0. In this study, however, the plasma concentrations after 24 days were significantly higher after intramuscular injection, consistent with the hypothesis of the depot effect of intramuscular phyllo- quinone (Loughnan & McDougall, 1996; see also section 4. They calculated from published studies that a realistic estimate of the terminal plasma half-time in neonates was 26–193 h (median, 76 h), as compared with 8–22 h (median, 14 h) in adults after intravenous administration (Øie et al. This longer terminal half- time may reflect the poorly developed organ systems of neonates and a reduced capacity to metabolize and excrete vitamin K (Stoeckel et al. The plasma profile of an oral dose of this preparation in five-day- old infants appeared to be similar to that of phylloquinone; after a 4-mg dose, a peak concentration of about 100 ng/mL was achieved after 3–4 h, before declining to about 30 ng/mL by 12 h (Shinzawa et al. The liver has often been assumed to be a major depot for vitamin K because it is the site of synthesis of the vitamin K-dependent coagulation proteins. Measurements of phyllo- quinone in livers obtained at autopsy from 32 adults in the United Kingdom revealed hepatic concentrations ranging from 1. Similar hepatic concentrations of phylloquinone were found in a smaller number of analyses of post-mortem samples from adults in Japan (10 ng/g) (Uchida & Komeno, 1988) and in The Netherlands (11 ng/g) (Thijssen & Drittij-Reijnders, 1996). The distribution of the various forms of vitamin K in the liver is quite different from that in plasma in that the major transport form, phylloquinone, represents the minority of total hepatic stores (about 10%); the remainder comprises bacterial menaquinones, mainly menaquinones- 6–13 (Shearer et al. The pattern of individual menaquinones in the liver varies considerably between individuals (Shearer et al. This proposal is supported by the finding that two menaquinones, -10 and -11, which are major forms in most liver samples (Uchida & Komeno, 1988; Thijssen & Drittij- Reijnders, 1996), are known to be synthesized by Bacteroides species which are predom- inant members of the human intestinal flora (Conly & Stein, 1992); yet menaquinone- 10 and menaquinone-11 do not make appreciable contributions to normal diets (Shearer et al. The concentration in the heart (~5 ng/g) [~10 pmol/g] is comparable to those in the liver, and even higher concen- trations (~13 ng/g) [~25 pmol/g] are found in the pancreas, but lower concentrations (< 1 ng/g) [< 2 pmol/g] were detected in brain, kidney and lung. These tissues do not appear to contain appreciable concentrations of menaquinones except for the short- chain menaquinone-4. Particularly high concentrations of menaquinone-4 relative to phylloquinone are present in the kidney, brain and pancreas. Although these and other tissues contain the enzymes of the vitamin K epoxide cycle (see Figure 1) and carry out vitamin K-dependent carboxylation of protein precursors, this would not appear to account for the tissue-specific accumulation of menaquinone-4 and may suggest a hitherto unrecognized physiological role for menaquinone-4 in certain tissues (Shearer, 1992; Thijssen & Drittij-Reijnders, 1996). Indeed, menaquinone-4 may arise by tissue synthesis from phylloquinone itself (Davidson et al.