Mark Corson

Charcoal absorbs strongly aromatic substances buy periactin 4mg with mastercard, such as : amino acids discount periactin 4mg with amex, which may be explained by virtue of the fact that the carbon-carbon spacings in graphite are almost of the same order as those present in benzene generic 4 mg periactin with visa. Weiss* used impregnated activated carbon with fatty acid or non-electrolyte thereby modifying and attributing special and improved adsorption characteristics. The molecular weight of dextran-gels vary considerably depending upon the extent of cross-linked nature. Note : These absorbents may be used both with or without binders, such as : colloidion. It has been observed that the rate of migration of a substance on a given adsorbent depends upon the solvent used ; therefore, the latter may be arranged in order of the elutive power, usually termed as the elutropic series as shown in the following Table 28. From actual experimental results it has been established beyond any reasonable doubt that the mix- tures of two or three solvents of different polarity mostly offer distinct and much improved separation as compared to chemically homogeneous solvents. In order to achieve very active layers, silica gel and alumina coated plates may be heated upto 150 °C for a duration of 4 hours and colling them in a dessicator. One end of the plate is then wetted with the developer by means of either ‘ascending-technique or the ‘descending-technique’ as shown in Figure 28. There are three major factors which essentially govern the ‘development of thin-layers’, namely : (i) Equilibration of the chamber (or chamber-saturation), (ii) Protection against oxidation (temperature and light), and (iii) Visualization. Equilibration of the Chamber The equilibration of the chamber or chamber-saturation is a vital factor to obtain reproducible Rf values. It may be achieved by allowing the solvent system to remain in the chamber for at least 1 to 2 hours so that the vapours of the solvent(s) would pre-saturate the latter adequately. Protection against Oxidation Both temperature and light augments oxidation and, therefore, ideally the following experimental parameters must be observed to obtain the best development of thin-layers, viz. Visualization As a result of both intensive as well as extensive research a number of organic and inorganic substances have been identified that positively demonstrate an ‘improved visualization’. Examples : Barium diphenylamine sulphonate ; 2,7-dichlorofluorescein ; Fluorescein (0. Example : Methyl esters of mixed fatty acid may be separated on loose-layer of alumina using suit- able solvent-system. To maintain uniformity, as a rule, plates of 20 cm height and 20-100 cm length with layers between 0. It could be expatiated with the help of the following typical example, namely : Example : Separation of mixture of fatty acids, cholesterols and their esters ; lecithins and polar lipids*** : S. Propanol : Ammonia Up-right (i) Resolution of polar lipids and lecithins ; (2 : 1) (ii) Carried fatty acids, cholesterol and its esters to the solvent front 2. Chloroform : Benzene -do- (i) Separated fatty acids and free cholesterols (3 : 1) (ii) Carried esters to the solvent front. The development is first carried out in the ascending direction using solvent-1 (see legend of Figure 28. The solvent is then eliminated by evaporation and the plate is rotated through 90°, following which ascending with the second solvent is accomplished. Example : Mixture of amino acids obtained from protein hydrolysates are separated by this method* and spots located by using Ninhydrin Reagent that forms a pink to purple product with amino acids. In this manner, the usual developing time of 35 minutes is drastically reduced to mere 10 minutes by acceleration. The following steps are to be adopted sequentially, namely : (i) Draw dividing lines 0. One may clearly visualize the beautiful separated bands in the latter as compared to the several odd and irregular-shaped spots in the former. Both the clarity of separation and the reproducibil- ity of the results are predominant in the latter technique. In actual practice, the resulting Rf value of the original compound together with the chromatographic results of the reaction are usually good enough to identify a compound accurately and precisely. Development in a solvent system consisting of benzene and ethyl acetate (2 : 1) would result in a clear distinction of cholestanol and reaction products of cholesterol with Br2. A buffered solution of phosphodiesterase is applied to the sample spot of cytidine dipohosphate glucose, which is subsequently covered with paraffin and allowed to stand for 45-60 minutes at 23°C. Chromatography of the resulting degradation products gives rise to cytidine 5-monophosphate and glucose 1-phosphate. After treating the compounds with the anhydride, it is absolutely necessary to dry the pate in the hood for several minutes so as to get rid of the trifluoroacetic acid that is produced as a by-product. Miller and Kirchner**** (1952) developed this combination thoroughly and employed it extensively for the separation of a large number of difficult types of compounds. Ikedaet al***** (1961, 1962) exploited this combination for the analysis of a variety of naturally occurring constituents, namely : (i) Citrus oils and other essential oils, (ii) Oestrogens in urine sample, (iii) Testosterone in urine sample, and (iv) Progesterone in plasma. These substances may also be detected as brown/dark brown spots when exposed to I2-vapours in a closed dessicator. Qualitative Evaluation The Rf value (Retention Factor) various separated solutes is determined accurately. The Rf value repre- sents the differences in rate of movement of the components duly caused by their various partition coefficients i. In order words, the Rf value (relate to front) is-‘the ratio between the distance starting point-centre of spot and distance starting point-solvent front’, thus it may be expressed as : Distance of centre of spot from starting point Rf =. Distance of solvent front from starting point Important Points : (i) Due to the always longer path of the solvent front, the Rf value is invariably lesser than 1.

Analysis revealed that the chemical diversity within the mutagenicity dataset was significantly less than the diversity of the marketed drugs purchase periactin 4mg on line. For the smaller drug set buy 4 mg periactin with visa, 750 ring systems were found in contrast to the 427 ring systems found in the Ames-test dataset cheap periactin 4mg online. The proportion of Ames negative to Ames positive counts is qualitatively indicated below each scaffold. The confidence interval of the proportions is 37 shown on the right of the scaffolds. In such a scenario, all possible fragments are examined to find those discriminative for a certain property, e. Most substructure mining methods use only part of the chemical information in a molecule, viz. Figure 9 shows a typical compound in standard chemical notation and two types of elaborate chemical representation. Elaborate chemical representation uses atomic hierarchies in addition to atom type labels, thereby including both general and more specific information. Atomic hierarchies are tree-like structures that consist of a root of a general atom label representing an atomic property, and branches of more atom-specific labels (specifiers). Aliphatic nitrogen and oxygen atoms were labeled as “small hetero atom” with specifiers for the atom type and number of connected hydrogens, as shown in Figure 9. Aliphatic sulfur and phosphorus atoms were labeled “large hetero atom” with an additional specifier for the atom type. Chlorine, bromine, and iodine atoms were labeled “halogen” with atom type specifiers (Figure 9). The “aromatic” setting used a special atom label and bond type to represent aromatic atoms and bonds, and attached a type specifier to aromatic heteroatom. Examples of aromatic atoms and bonds are shown in chemical representation I in Figure 9. The “planar” setting used a special atom label and bond type for atoms and bonds in aliphatic five- and six-membered rings or aromatic rings, including atom type specifiers. An additional atom specifier for the atom type was connected to heteroatoms and halogens, and a specifier for implicit hydrogens was connected to heteroatom. Standard and elaborate chemical representations were used to extract substructures 55 Chapter 2 from mutagenicity data, both with and without considering non-linear fragments. The dataset consisted of 4,069 compounds from the Chemical Carcinogenesis Research 41 Information System database. Compounds were categorized as non-mutagens if all mutagenicity tests had a negative outcome. Atom labels are carbon (C), nitrogen (N), oxygen (O), small heteroatom ([N,O]), halogen (X), chorine (Cl), aromatic atom (A), planar atom (Pl), and number of implicit hydrogens (H1). A decision list was constructed (Figure 10) by using the fragment with lowest p-value to split the set into two subsets (one that contained the fragment and one that did not). The p-value of a fragment was defined as the probability to find a statistical association with mutagenicity based on chance alone. It was calculated from the amount of mutagens versus non-mutagens that are detected using that fragment. For the subset that did not contain the fragment, p- values were recomputed and the next most mutagenic fragment was used to split this set. In case of multiple fragments with the lowest p-value, the largest fragment was used. The process was repeated as long as the new set had more than 60% mutagenic -20 compounds. If the best-selected fragment had a p-value of more than 10 , no further splits were made. From all methods, the use of elaborate chemical representation combined with detection of nonlinear fragments proved best: mutagens were detected with a sensitivity of 84%. The resulting decision list (Figure 10) consisted of six non-redundant discriminating substructures, starting with a polycyclic planar system that described at least three rings, and consisted of 11 planar atoms connected by planar bonds. The next most discriminating fragment was a nitrogen atom double- bonded to a nitrogen or oxygen, followed by a 3-membered heterocycle (aliphatic epoxides and aziridines), and then an aliphatic halogen (chlorine, bromine, and iodine). The second-last fragment was an aromatic primary amine and the list ended with a heteroatom-bonded to a heteroatom fragment. Some of these substructures proved to be very similar to the general toxicophores derived previously by the authors in a 42 laborious approach. For instance, the most discriminative fragment for mutagenicity would not have been detected by other methods, since the planar atom notation proved essential. Moreover, the importance of wildcards is underlined by their presence in all six substructures. Since the list contained two branched and one cyclic substructure, all possible graphs must be considered in substructure mining. Arrows indicate the direction to follow if a substructure is (Y) or is not (N) present in a compound. The number of mutagens, the total number of compounds, and the percentage of mutagens is indicated for each subset (right). A set of 119 kinase inhibitors for at least 18 different targets, was fragmented into ring systems and linkers, and frequencies of occurrence were analyzed. Since bi- and tricyclic ring systems were relatively rare in the fragmented set, only monocyclic rings were considered. The authors found that the four rings benzene, pyridine, pyrimidine, and pyrrole, comprise almost 90% of monocyclic ring occurrences in the fragmented data set.

Dose Intravenous injecton Adult- 100 mg/m2 body surface area every 12 h for seven days order periactin 4mg line. Child- 100 mg/m2 body surface area twice daily by rapid injecton or 100 mg/m2 body surface area daily by contuous infusion given by 5 to 10 days periactin 4 mg cheap. Contraindicatons See notes above and consult literature; hypersensitvity; pregnancy (Appendix 7c) and lactaton (Appendix 7b) 4mg periactin overnight delivery. Precautons See notes above and consult literature; uric acid level monitoring recommended; hepatic impairment (Appendix 7a). Contraindicatons Known hypersensitvity, cardiac disease, pregnancy (Appendix 7c), lactaton, neonates. Adverse Efects Infusion reactons, cardiotoxicity, bone marrow suppression, liver impairment, nausea and vomitng, reversible alopecia, stomatts, conjunctvits, keratts, mucosits, discolouraton of body fuids, local skin reactons and tssue damage, secondary leukemias. Storage Store protected from light, in well closed containers at temperature between (15- 30⁰C); Store intact vials of soluton under refrigeraton at 2-8⁰C. Use the soluton prepared using the liquid stated on the label immediately afer preparaton but, in any case, within the period recommended by the manufacturer when prepared and stored strictly in accordance with the instructons of the manufacturer. Etoposide* Pregnancy Category-D Schedule H Indicatons Refractory testcular tumours; acute leukaemia; malignant lymphoma; lung cancer. Dose Intramuscular injecton Adult- Initally 50 to 100 mg/m2 body surface area daily by infusing over 30 to 60 min. Oral Adult- 100 to 200 mg/m2 body surface area from day 1 to 5 taken on empty stomach, thereafer no treatment for 3 to 4 weeks. Contraindicatons See notes above and consult literature; hypersensitivity; severe liver dysfunction; pregnancy (Appendix 7c) and lactation (Appendix 7b). Precautons See notes above and consult literature; hepatc impairment (Appendix 7a); interactons (Appendix 6c); renal impairment (Appendix 7d). Dose Intravenous injecton Initally 12 mg/kg body weight once a day for 4 days, max. If tolerated well without toxicity 6 mg/kg body weight can be given on 6th, 8th, 10th and 12th day. Contraindicatons See notes above and consult literature; bone marrow depression; pregnancy (Appendix 7c) and lactaton (Appendix 7b). Precautons See notes above and consult literature; lactaton; pelvic irradiaton; renal impairment; hepatc impairment (Appendix 7a); interactons (Appendix 6c). Storage Store protected from light in single dose container at a temperature not exceeding 30⁰C. Folinic Acid* Pregnancy Category-A Indicatons High-dose methotrexate therapy (‘folate rescue’); inadvertent overdose of methotrex- ate; with 5-fuorouracil in the palliatve treat- ment of advanced colorectal cancer. Dose Preventon of methotrexate induced adverse reactons; started 24 h afer treatment with methotrexate by intravenous infusion or by intravenous injecton. Precautons Avoid simultaneous administraton of methotrexate; not indicated for pernicious anaemia or other megaloblastc anaemias due to vitamin B12 defciency; pregnancy (Appendix 7c) and lactaton; interactons (Appendix 6c). Adverse Efects Hypersensitvity reactons; rarely, pyrexia afer parenteral use; wheezing; swelling of facial features. Gemcitabine* Pregnancy Category-D Schedule H Indicatons Adenocarcinoma of pancreas. Dose 1g/m2body surface area for over 30 min once a week for up to 7 weeks, if not tolerated reduce or withhold. Afer one week rest administer by infusion once weekly for three weeks, withhold for 4th week before repeatng. Contraindicatons Pregnancy (Appendix 7c); concurrent radial radiotherapy; hypersensitvity; lactaton. Precautons Gemcitabine is not recommended for patents who can have potentally curatve surgery. There is insufcient evidence about its use for second-line treatment of pancreatc adenocarcinoma, hepatc impairment; renal impairment, interactons (Appendix 6c). Adverse Efects Nausea, vomitng, oral mucosits, hyperuricaemia, bone marrow suppression, alopecia, thromboembolism, fu like syndrome; edema; thrombocyathemia; somnolence; hematuria; dyspnoea; loss of appette. Adverse Efects Acute-nausea and vomitng; chronic fuid retenton with ankle and periorbital edema, diarrhoea, myalgias, congestve heart failure. L- Asparaginase* Pregnancy Category-C Schedule G Indicatons Acute lymphoblastc leukaemia. Dose Intramuscular, intravenous or subcutaneous injecton Exclusively in acute lymphoblastc leukaemia. Contraindicatons See notes above and consult literature; pregnancy (Appendix 7c) and lactaton (Appendix 7b). Melphalan* Pregnancy Category-D Schedule H Indicatons Breast carcinoma, multple myeloma, advanced ovarian carcinoma, malignant melanoma, polycythaemia vera. Alternatvely 10 mg daily for 7 days (total dose 70 mg), repeat if required afer blood counts partcularly neutrophils and platelets. Contraindicatons Pregnancy (Appendix 7c); hypersensitvity; myelosuppression; lactaton. Adverse Efects Nausea, vomitng, oral mucosits, hyperuricaemia, bone marrow suppression, alopecia, thromboembolism, leucopenia; menstrual irregularites; haemolytc anaemia. Contraindicatons See notes above and consult literature; hypersensitvity; pregnancy (Appendix 7c) and lactaton (Appendix 7b). Precautons See notes above and consult literature; monitor blood count; uric acid levels; renal impairment and hepatc impairment (Appendix 7a); interactons (Appendix 6c). Dose Oral Choriocarcinoma: 15 to 30 mg daily for 5 days repeat 3 to5 full courses afer 1 week.

What do you understand by ‘direct titration method’ in the context of Aqueous Titrations? Discuss in details the procedure involved in the assay of : (a) Sodium carbonate (b) Sodium salicylate tablets generic 4mg periactin fast delivery. Justify the statement with the help of assay of the following pharmaceutical substances : (a) Zine Oxide (b) Milk of Magnesia cheap periactin 4mg otc. Rosenthal cheap periactin 4mg fast delivery, D, and P Zuman, ‘Acid-Base Equilibria, Buffers and Titration in Water’, In Treatise on Analytical Chemistry, ed. Ahuja, S, Impurities Evaluation of Pharmaceuticals, Marcel Dekker, New York, 1988. Evidently, these compounds posed two vital problems of quality control, both in pure and dosage forms by virtue of their inherent characteristics, namely : (a) poor solubility, and (b) weak reactivity in aqueous medium. Initially, the above two problems were usually circumvented in the following manner : Example 1 : Amine salts—It is first changed to the water-soluble free base, extracted with an appro- priate organic solvent and treated with an excess volume of standard acid ; subsequently, the solvent was evaporated, and the remaining acid determined with a standard base. Example 2 : Sodium salts—It is first acidified to release the water-insoluble organic acid, extracted with a suitable organic solvent, the solvent was removed and the residue was subsequently dried and weighed. Example 3 : Nitrogen containing compounds—They are estimated by micro Kjeldahl’s Method. Nevertheless, such specific quantitative methods gave rise to certain serious anomalies and draw- backs. In order to overcome these shortcomings the non-aqueous titrations were introduced. The reason being that in aqueous medium and at higher Kb values (> 10–6) the solvent water competes progressively with the basic species in solution for the proton of the solvent. Hence, from the above definitions it may be implied that : (a) an acid : could be either an electrically neutral molecule e. H+ + A – Acid Basic Solvated Conjugate solvent proton base of acid Perchloric acid displays more strongly acidic characteristics than a weak acid, for instance : acetic acid when dissolved in a weakly basic solvent. Perchloric Acid : It is a very strong acid and when it is made to dissolve in acetic acid, the latter can behave as a base and forms an ‘onium ion’ after combining with protons donated by the perchloric acid. Pyridine, a weak base, when dissolved in acetic acid, the latter exerts its levelling effect and subsequently increases the basic characteristics of the pyridine. Therefore, it is practically feasible to titrate a solution of a weak base in acetic acid against a mixture of perchloric acid in acetic acid. Thus, a sharp end point is achieved which otherwise cannot be obtained when the titration is performed in an aqueous medium. In short, it is possible to titrate mixtures of two or three components selectively with a single titration by wisdom of the right choice of solvent for the non-aqueous titrations. Now add 30 ml acetic anhydride and make up the volume to 1 litre with glacial acetic acid and allow to stand for 24 hours before use. It usually undergoes a spontaneous explosive decomposition and, therefore, it is available always in the form of a solution. Add 25 ml of glacial acetic acid and attach a reflux condenser fitted with a silica-gel drying tube. It is, however, necessary to mention here that the same indicator must be used throughout for carrying out the standardiza- tion, titration and neutralization of mercuric acetate solution. Hence, it is always advisable to carry out standardization and titration preferably at the same temperature. In a situation where these temperature parameters cannot be achieved, the volume of titrant may be corrected by the application of the following formula : Vc = V [1 + 0. For the sake of convenience these typical titrations can be catego- rized into two broad groups, namely : (a) Acidimetry in Non-aqueous Titrations—It can be further sub-divided into two heads, namely : (i) Titration of primary, secondary and tertiary amines, and (ii) Titration of halogen acid salts of bases. Methlyldopa In general, the reaction taking place between a primary amine and perchloric acid may be expressed as follows : R. Calculations : The percentage of methyldopa present in the sample is given by : ml 0. Blank Titration : It is usually carried out to account for the possible reaction of atmospheric moisture with the titrant perchloric acid and also to check the titrant being employed to bring about the blue-green end-point. Calculations : The percentage of methacholine chloride in the sample may be calculated by the following expression : ml 0. Potentiometric Titrations These non-aqueous titrations may also be carried out with the help of potentiometric titrations which technique shall be discussed at length elsewhere in this book. It is always preferred to first ascertain the equivalence point of a given neutralization reaction potentiometrically (i. In actual practice, however, there are quite a number of non-aqueous titrations of pharmaceutical substances either in pure or in dosage forms that can be successfully performed potentiometrically. Titration of Halogen Acid Salts of Bases In general, the halide ions, namely : chloride, bromide and iodide are very weakly basic in character so much so that they cannot react quantitatively with acetous perchloric acid. In order to overcome this problem, mercuric acetate is usually added (it remains undissociated in acetic acid solution) to a halide salt thereby causing the replacement of halide ion by an equivalent amount of acetate ion, which serves as a strong base in acetic acid as shown below : 2R. Cool, add 10 ml of mercuric acetate solution, two drops of crystal violet solution and titrate with 0. Cognate Assays The following estimations of various pharmaceutical substances can also be carried out by the aforesaid procedure (Table 5. The wide spectrum of such organic compounds in- clude : anhydrides, acids, amino acids, acid halides, enols (viz.