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Analytical Profiles of Drug Substances and Excipients Vol 22 1993 ISBN 0122608224 9780122608223 – Windows 10 1703 download iso itachi pfpa form
In the or-form, chains are formed by O-H NH bonds. The IR technique was also used to study the properties and structure of divalent manganese, cobalt and nickel complexes with p-derivatives of benzoic acid The complexes were prepared, characterized and their stability constants determined.
The acid dissociation constants, the dependence of the thermal stability on the nature of the metal and the p-substituent and the lattice parameter were determined for the complexes. The 0 – H stretching frequencies of p-aminobenzoic acid together with many p- and msubstituted benzoic acids were measured in dil CCl, solution The validity of the latter for substituents without.
The assignment of the chemical shifts to the different protons presented in Table 8. Table 8: Assignment of protons chemical shifts. Chemical shift 6 5. The carbon chemical shifts assigned on the basis of the theories of. Figure 9. I Figure Table 9: Assignment carbon chemical shifts. In a study on the importance of. Thus for a series of the general formula below, the p-or m-substituent X induces changes in the 13Cchemical shifts at the a-C atom which correlate with substituent parameters via the d.
The inductive effect of X is largely. Removal of the n-electrons of the carbonyl by complexation or protonation removes the possibility of a n-polarization mechanism and results in a change in the sign of PI values. The resonance effect of X varies considerably from one series to another, and is determined by both the inductive and resonance effects of the Z group.
All compounds that are not highly hindered show systematic changes in chemical shifts that can be correlated with inductive and resonance parameters by using a dual-substituent-parameter analysis. In these cases, resonance effects play a slightly more important role than do inductive effects.
Highly hindered compounds show no systematically significant correlations although qualitative trends are discernible. The absence of correlation reflects the different extents to which steric constraints allow or inhibit lone-pair delocalization as the deman changes with substituent. Scheme 1 shows a proposed fragmentation pattern of PABA. Svnthesis A. Mallonee 21 synthesized p-aminobenzoic acid by agitating a mixture of water, sodium hydroxide, aqueous ammonia and p-nitrobenzoic acid charged into a steel make-.
The irradiation was carried for 6 hr at 8 2 O using Hg lamp Scheme 2. It was deduced that the aminating agent was the amino radical 23 Scheme 2.
Biosvnthesis p-Aminobenzoic acid is a growth factor for certain microorganisms. This moiety is incorporated in foIate conenzymes in bacterial biosynthesis Scheme 3. Genetic studies have led to the characterization of two genes, pabA and pabB The pabA gene encodes PabA, a kDa protein with high sequence homology to the TrpG component in oaminobenzoate required for anthranilate synthesis biosynthesis Each of PabA and TrpG is capable of encoding a glutaminase activity, providing nacent ammonia for the two regiospecific chorismate aminations.
The pabB gene product, SlkDa 30 is substantially homologous to the trpE. The latter protein catalyses the ammonia-dependent chorismate amination to 2-amino-2deoxy-isochorismate and its subsequent aromatization by syn elimination of the elements of pyruvate 32, The studies carried on PabB anticipated that this protein catalyses similar regiospecific amination and then aromatization of 4-amino-4deoxychorismate, which is finally converted to PABA by crude bacterial extracts Another protein has been recently reported 35,36 with substantial homoglogy to the TrpE and PabB.
The enzyme, known as isochorismate synthase, catalyses the interconversion of chorismate and its dihydroaromatic isomer isochorismate without aromatization 37 , at the start of the enterobactin biosynthesis pathway Studies by Nichols et. This activity was proposed to act on a diffusible intermediate generated by PabB action and to convert it to the aromatic amino acid product PABA and is designed as enzyme X. This is confirmed by a recent report by Ye et. Working on the purified PabB, they confirmed that PabB needs an additional protein, enzyme X, to convert chorismate and ammonia to paminobenzoate.
The enzyme X was purified to near homogeneity from E. Dissolve 0. Each ml of 0. A method is performed for the assay of 4-aminobenzoic acid 42 by titration with 0. The product is described and its solubilities and m. Identity tests and limit tests for insoluble matter, color of solution, heavy metal, CP SO:-?
The pKb value of 4-aminobenzoic acid and other bases in acetic acid ‘acetous’ pKb are reported 44 , and differentiating titrations of five pairs of bases in acetic acid medium are considered; a glass-calomel LiCIO, bridge system is used and the titrant is HCIO, in acetic acid. It is concluded that differentiating titration of bases is possible if the difference between their pKb values exceeds 4. A bright platinum indicator electrode was used. If more dilute reagent solution are used, there is some loss of accuracy.
Kumar and Indrasenan 43 have determined p-aminobenzoic acid used in pharmaceuticals and cosmetics , by a. An indirect volumetric method for the determination of 4-aminobenzoic acid and other amines is described The method is based on the oxidizing action of NaC1O2, Under the reaction conditions, the action of NaCIO, on the amine is directly proportional to its concentration. The amine solution is prepared by dissolving of weighed amount in HC1, and aliquot is transferred into ground-glass stoppered Erlenmeyer flasks, with addition of a measured excess of 0.
KI solution is added and the solution is agitated and titrated with 0. The NaClO, solution must be prepared sometime before use, to allow establishment of a constant concentration and it is calibrated against 0. The use of chloramine-T for the estimation of 4aminobenzoic acid has been reported The method is claimed to be simple and accurate and determines milligram amounts of the drug. Milligram amounts of the sample were allowed to react with a known excess of chloramine-T in acidic medium at room temperature for minutes.
After the completion of reaction, the unconsumed reagent was back titrated iodometrically. The accuracy of the method is k 0. Jayaram and Gowda 48 reported a method for the assay of 4-aminobenzoic acid with aromatic N-haloamines.
The method involves the use of chloramine T, bromamine-T the bromo-analogue of chloramine-T or bromamine-B the demethyl analogue of bromamine T as oxidimetric reagents.
An aliquot of the test solution containing 0. A titrimetric method suitable for the determination of pg of p-aminobenzoic acid was developed The method is based on iodination of the compound. The resulting iodide, after removal of excess iodine, is oxidized with Br to iodate which is determined by the Leipert amplification procedure. Delgado 50 have reported a coulometric determination of 4-aminobenzoic acid and other aromatic amines. The pH is a dominant factor in the titration of the amine with bromine.
Displacement of certain substituent groups e. Suitable pH, and the equivalent of bromine per molecule, for 4-aminobenzoic acid are 5 and 6, respectively. The polarographic behavior of 4-aminobenzoic acid, and other substituted benzoic acids, in aprotic dipolar solvents are studied 51 by d.
The advantage of ax. There is a linear relation between the reduction peaks of the acids and their concentration with a lower detection limit of X 10JM. A direct-injection enthalpimetric method for the determination of 4-aminobenzoic and other aromatic amines has been reported The method is based on diazotisation or nitrosation of the amine, the heat of the reaction being measured.
The double injection method is used; the difference in the temperature jumps observed on making the two injections of reagent is correlated with the amine concentration. The procedure was verified by determination of 4-aminobenzoic acid and other amines. Several theories and practical aspects of the hydrosol preparation, protocols and sample preparation procedures, and their effects on the sensitivity and reproducibility of the Raman signals are discussed. The effect of acidity on SERS signal intensity is shown to depend on the time of the observation of the Raman spectra, illustrating the relevance of time to quantitative SERS data.
The identification power of SERS at trace level of closely related compounds p-nitrobenzoic acid, p-aminobenzoic acid and aniline is illustrated. The determination of 4-aminobenzoic acid in PreSun lotion using surface-enhanced Raman analysis has been published The plates were then vacuum-coated with a nm layer of Ag.
The lotion was diluted with ethanol to give two solutions expected to contain 6 and 14 ppm of p-aminobenzoic acid. Portions 1 pl of these solutions and standards were applied. For the measurement of the surface-enhanced Raman scattering, the plates were illuminated from the back with light from a Kr laser The scattered light was transmitted to the photomultiplier tube with a second optical fiber and the p-aminobenzoic acid peak at cm-‘ was measured.
In the range 4 to 16 ppm of p-aminobenzoic acid, the results were correct to within 3 ppm; no other constituents of the lotion interfered. The other hydrolysis product diethylaminoethanol did not interfere with the determination of p-aminobenzoic acid. Liu 58 determined p-aminobenzoic acid in procaine injection by UV spectrometry. Procaine injection were mixed with 60 ml potassium tartrate and water to ml. Four ml of the solution was further diluted with water to 10 ml, which was extracted with ether.
The organic phase was dried, dissolved in 10 ml water and analyzed at nm for the determination of p-aminobenzoic acid. The quantitative determination of p-aminobenzoic acid and other compounds present in a pharmaceutical preparation, antiseborrhoeic shampoo was reported The drug was determined in a 5 g sample by dilution and measurement of the absorbance of the solution at nm. The injections were diluted with distilled water and the absorbance was measured at , The p-aminobenzoic acid concentration was inversely related to AA,,.
Wang 6 1 have applied secondary chemical equilibria in reversed-phase column partition chromatography, for the determination of procaine hydrochloride injections and quality control of 4-aminobenzoic acid. The injection solution containing 10 mg of procaine-HC1 was applied to an 8 g silanized siliceous earth support with 5 ml of hexanol as stationary phase previously percolated with 20 ml of 0.
The eluate was diluted with water to 50 ml and p-aminobenzoic acid was determined by absorbance measurement at nm vs water. Procaine was then eluted from the column with 60 ml of 0. Equations for computation of procaine and p-aminobenzoic acid concentrations are presented.
To an ice-cold solution 5 ml of 4-aminobenzoic acid in 0. The fluorescence was measured at nm excitation at nm. Samples and solutions containing 0. Their extinctions were determined in a Pulfrich photometer using an S filter. A curve of extinction values versus the content of the drug was given.
The detection of a mixture of p-aminobenzoic acid and procainamide is also reported The drug was photocolorimetrically determined 64 using its color reaction in acid media with glutaconaldehyde, the product of the alkaline decomposition of Npyridylpyridinuim chloride-HC1. Thirty minutes later, the absorbance was measured at nm.
The drug was also determined 65 by diazotisation with 2N-HCl 0. The optimum pH for maximum color development is in the range of 7 to The extinction of the solution was measured at nm.
The calibration graph was rectilinear in the range of 0. The absorbance of the dye was measured at nm A photometric determination of 4-aminobenzoic acid was reported To 1 ml of solution containing 10 mg of the drug were added 5 ml of M-HCl and 1 ml of 0. After 2 minutes, 2 ml of 0. After further 3 minutes, the solution is diluted to 50 ml with water and the extinction is measured at nm.
An assay for the measurement of urinary 4-aminobenzoic acid in the oral pancreatic-function test was reported The measurement of the acid in urine after oral acid administration of N-benzoyl-L-tyrosylaminobenzoic has been studied with 4-dimethylaminocinnamaldehyde as chromogenic reagent.
The latter reacts with 4-aminobenzoic acid in acidic solution pH 1. The calibration graph is rectilinear for up to pg m1-I of p-aminobenzoic acid in the sample. Several colorimetric and fluorometric methods were described for the quantitation of primary arylamines These include: formation of N-substituted derivatives of p 1 nitrophenylazobenzamide. Condensation with glutaconic dialdehyde to yield 3 colored Schiff’s base. Bratton-Marshall method for urinary 4-aminobenzoic acid have been evaluated Urine samples are hydrolysed with HC1 for.
Portion of the hydrolysate are diluted to 5 ml and treated with 0. The calibration graph is rectilinear for 0. The method was intended as a test for excocrine pancreatic function after administration of bentiromide.
Bando et a1 71 have reported an enzymic method for selective determination of 4-aminobenzoic acid in urine. Urine 1 ml was heated at loo0 for 2 hours with 4M-KOH, then mixed with anhydrous acetic acid and incubated at for 20 minutes with 4-aminobenzoate hydroxylase 50 miu.
After addition of g 1-‘ trichloroacetic acid, 0. A colorimetric determination of 4-aminobenzoic acid and other primary aromatic amines using N-alkyl aminophenol and iodine has also been reported The determination of urinary 4-aminobenzoic acid with fluorescamine in the pancreatic function test with bentiromide have been published An experimental procedure is described 75 whereby addition of poly acry1ic acid to solution of 4-aminobenzoic.
NH, : H,O Solvent System Cyclohexane: ethyl acetate: chloroform: acetone Cyclohexane: ethylacetate: methanol Cyclohexane: ethylacetate: chloroform and Alkaline or neutral solvent systems w m. Karnes et a1 76 reported a comparative evaluation of two substrates for urinary determination of 4-aminobenzoic acid by room-temperature phosphorimetry. The substrates considered were: i filter paper S. In each instance, calibration graphs were rectilinear in the range 0 to 40 mg I-‘ of 4-aminobenzoic acid.
Karnes et a1 77 have also determined 4-aminobenzoic acid in urine by room-temperature phosphometry, with application to the bentiromide test for pancreatic function. The drug was derivatized with fluorescamine. The optimum pH, buffer concentration and phosphorescence characteristics are discussed. Table 10 summarizes the several thin-layer chromatographic methods reported on p-aminobenzoic acid Two more TLC methods have also been reported 89, Cumpelik 9 1 described a gas liquid chromatographic system for analysis of p-aminobenzoic acid and other multiple absorber sunscreens.
The gas chromatographic retention times of different UV absorbing agents used in sunscreen preparations are compiled as an aid to identification in cosmetic samples. The temperature was programmed from to at. Table High performance liquid chromatography of p-aminobenzoic acid Support and column pBondapak C,, Mobile phase Flow rate 1. All the samples were silanized and centrifuged.
Wurst et a 92 developed a gas-chromatographic 1 method for determining trimethylsilyl derivatives of 4aminobenzoic acid and other carboxylic acid in mixtures of biological materials. The separation was performed on 1,5-bis m-phenoxypheny1 – 1,1,3,3,5,5-hexaphenyltrisiloxane as stationary phase.
Its efficiency was compared with that of SE Nitrogen carrier gas, flame ionisation detection, and a temperature programming mode were used. Harahap et a1 93 reported a gas-chromatographic method for the analysis of 4-aminobenzoic acid in the thermoplastic aromatic polyamides after alkali fusion.
The sample of the thermoplastic aromatic polyamide, containing equimolar ratios of 4-aminobenzoic acid and other acid was subjected to alkali fusion at ” for 2 hours with potassium hydroxide-sodium acetate 1. The mixture was cooled and isophthalic acid was precipitated by adjusting the solution to pH 7. The precipitate was filtered off and isophthalic acid was derivatized to its dimethyl ester with methanolic BF, reagent.
The remaining aqueous layer was adjusted to pH 6 and paminobenzoic and 3-aminobenzoic acid were extracted into chloroform and derivatized to their TMS derivatives. Separation of the three derivatives was carried out on a column 12 ft X 0. The 3 and 4-aminobenzoic acids are separated on a. Randau and Schnell 95 have separated 4aminobenzoic acid on columns 25 cm X 1.
The MP was superior, optimal separation occuring at ; on the M column, no separation was achieved at the lower temperature and only partial separation at 50 O. It is concluded that the macroporous resins permit separation only achieved with the gel resins at much smaller particle size and greater column pressure, 5. Another method has also been published Standard solution containing 0.
PABA is used topically as a sunscreen agent usually in a concentration of. Its preparations are therefore effective in preventing sun burns but ineffecitve in preventing drug-relating or other photosensitive reactions associated with UVA light; combination with a benzophenone may give some added protection against such photosynthetic disorders. Application of this solution once daily for 30 days did not give rise to cutaneous or systemic toxic symptoms.
PABA has no protective effect when given by mouth. Some studies were reported on the improvement of the test specificity as well as comparison and combination with established or new tests Development of vitiligo in sunexposed areas following adminstration of aminobenzoic acid by mouth was reported 1 Precautions Aminobenzoate sunscreen agents should not be used by patients with previous experience of photosensitive or allergic reactions to chemically-related drugs such as sulfonamides, thiazide diuretics and certain local anesthetics, particularly benzocaine.
PABA is readily absorbed from the gastrointestinal tract after oral adminstration 2,3. The percutaneous absorption of PABA was determined in vitro through hairless guinea pig skin The absorption of PABA was greater through nonviable skin. Illel et. Using their skin model they compared the percutaneous absorption in appendage-free skin relative to normal skin.
The results confirmed that appendageal diffusion is the major bathway in hairless rat skin. In the absence of follides, the steady state flux and the amounts diffusing in one or two days are times lower than in normal skin. PABA serum and urine concentrations were measured in patients with normal, pathologic and pharmacologically inhibited pancreatic function A maximum increase of In patients with exocrine pancrease insufficiency or those with pharmacologically inhibited exocrine pancrease resulted in a significantly reduced PABAserum concentration.
Thyroid dysfunction was found to affect the small intestinal absorption of some drugs including p-aminobenzoic acid. Thus, examination of the effect in the i siru recirculating n perfusion and everted sac methods showed that the intestinal absorption of passively absorbed drugs were depressed in hyper- and hypothyroid rats Studies using the same above methods were undertaken by Miyagi et.
The transfer of p-acetamidobenzoic acid was not influenced by C o k When PABA was orally administered in the rat treated with Con A, the plasma concentrations of PABA and of acetamidobenzoic acid increased compared with control. No influence of Con A was observed in the I. The plasma concentrations of acetamidobenzoic acid was unchanged when this PABA metabolite was orally or I.
Branco and Torres determined the levels of some water-soluble vitamins in Planorbidae. The determinations were carried out in total snail and in digestive tract extracts of Biomphalaria glubrata. While some vitamins like folk acid showed higher levels in the digestive tract extract than in the total snail extract, the concentration of other vitamins including PABA produced higher levels in the total snail extracts.
Fendrich et. Greatest concentrations of PABA were noted in the kidneys, liver and intestines with almost none in the brain. Koren et al. PABA distribution volume in CF patients was smaller, although not significantly so, than the controls. PABA is mainly metabolized in the liver 4 and kidney It is conjugated with glycine to form p-aminohippuric.
Small amounts of p-aminobenzoyl glucuronide, pacetamidobenzoyl glucuronide and traces of p-acetamidohippuric, p-acetamidobenzoic acid and unchanged aminobenzoic acid are also detected in urine 2, Chan et al. PABA may be detected in urine as a metabolite of amethocaine, benzocaine and procaine 2. The metabolism of PABA is reported to be influenced by many factors. Acetyltransferase activities in the small intestinal mucosa and the liver were increased in rats treated with cancanavalin A These results suggest that concanavalin A will facilitate the metabolism of PABA in the small intestine and liver of rat.
The effect of ethanolamine on the acetylation of PABA was studied in adult rats The results showed that ethanolamine significantly increases the acetylation capacity of tissues. Griffeth et. Moreover, the i vivo reaction of acetylation was n found to be significantly decreased by model trauma. This effect on in vivu pharmacokinetics appeared to be correlated closely with trauma’s influence on the conjugating enzymes and relatively independent of the post-traumatic response of the necessary co-substrates.
It is thus suggested that traumatic injury appears to have wide-ranging effects on a variety of determinants of hepatic drug metabolism. In an overview on renal disease and drug metabolism, Gibson reported that in a diseased kidney the metabolism of PABA, and other drugs known to be metabolized in the kidney, is reduced. Renal disease, therefore, has its potential to alter not only the renal clearance of unchanged drug but also may substantially modify the metabolic transformation of drugs in both the liver and the kidney.
The tissue distribution of acetyltransferase with PABA as a substrate in humans was investigated by Pacifici et. All tissue specimens catalyse the acetylation of PABA at a significant rate. These results together with the detection of Nacetylating activity in the skin of other experimental animals and humans , suggest that the skin may play an important role in the metabolism of the drug and other armatic amines. Relatively high levels of acetyl transferase activity was also found in urinary bladder cytosol of humans A number of other studies on the metabolic acetylation of PABA appeared in the literature.
These include reports on the genetic control , kinetics , and inhibition studies of the acetyltransferase enzyme. Scheme 5 lists the major metabolites of PABA. PABA is mainly excreted in urine as its conjugate, paminohippuric acid together with small amounts of paminobenzoyl glucuronide, p-acetamidobenzoyl glucuronide. Traces of p-acetamidohippuric acid, p-acetamidobenzoic acid and unchanged benzoic acid are also detected in urine 2. The PABA clearance was similar in the control 2. Acknowledgements The authors would like to thank Mr.
Tanvir A. Butt for typing this manuscript. Rizk, M. Walash and N. Rabou, Arch. Ed 6, 26 Radhakrishnamurty and G. Rao, J. India , 56, 79 Mynka and M. Lyutaya, Farm. Kiev , 4,38 Lai and R. Marsh, Acta Crystalloer. Killean, P. Tollin, D. Watson and D. Young, W, 19, Anulewicz, G.
Haefelinger, T. Krygowski, C. Regelmann and G. Ritter, Z. Inomata and T. Moriwaki, Nippon Kaeaku Zasshi, 9, Theoret, Spectrochim. Acta, Part A, 27, 11 Lauransan and J.
Corset, Ann. Paris , 4, Churagov, D. Gambarov and Kh. Mamedov, Koord. Khim 17, Bromilov, R. Brownlee, D. Craik, P. Fiske, J. Rowe and M. Sadek, J. Perkin Trans. Sibi, E. Prince, J. LeMelle and R. Lichter, Spectrosc. Registry of Mass Spectral Data, E. Stenhogen, S. Abrahamsson and F. Mallonee, U. Hashimoto, J. Sunakoto and H. Fujii, Japan. Sakumoto, Bull. Walsh, M. Erion, A. Walts, J. Delany and G. Berchtold, Biochemistry, 26, McLeish, P.
Wookey and K. Mortimer, Biochem. Kane and H. OBrien, J. Huang and F. Gibson, J. Kaplan and B. Nichols, J. Biol, , Goncharoff and B. Yanofsky, T. Platt, I.
Crawford, B. Nichols, G. Christie, H. Horowitz, M. VanCleemput and A. Wu, Nucleic Acids Res. Policastro, K. Au, C. Walsh and G. Berchtold, Am, Chem. Teng and B. Ganem, J. Teng, B. Ganem, S. Doktor, B. Nichols, R. Bhatnagalr and L. Vining, J. Elkins and C. Ozebberger, T.
Brickman and M. Mcintosh, Bacteriol. Liu, N. Quinn, G. Berchtold and C. Walsh, Biochernisa, 29, Walsh, J. Liu, F. Rusnak and M. Sakaitani, Chem. Nichols, A. Seibold and S. Doktor, J. Ye, J. Liu and C. Walsh, Proc. Keiner, R. Huettenrauch and A. Eichhorn, Zentbl. Kumar and P. Indrasenan, J. Castellano, T.
Medwick, J. Shinkai and L. Bailey, J Pharm. Arora, and C. Bhatnagar, Z. Albert, V. Cimpu, M. Valeanu and El. Radulescu-Jercan, Rev. Roumaine Chem. Shukla, S. Ahmed and R. Dwivedi, Proc. India, Sect. A, 55, Jayaram and N. Gowda, Analyst, , El-Samman and D. Amin, Microchem. Delgado, Rev. Petrov, L. Karaseva and T.
Bogoslovskaya, Zh. Zvesti 33, Laserna, E. Torres and J. Winefordner, Anal. Acta , Narayanan, J. Bello, D. Stokes and T. Vo-Dinh, Analusis, 19, Kurenman, F. Sheyanova and V. Boyarkina, Khim. Dam and L. Veinbergs, M. Pormale, N. Kashkina and E. Simsone, Latv. PSR Zinat. Akad Vestis.
Liu, Yaowu Fenxi Zazhi, 2, Bertini, V. Nuti and G. Linari, Bull. Zhang, Yaoxue Tongbao, 20, Wang and X. Li, Yaowu Fenxi Zazhi. Taniguchi, T. Yoshida, T. Kobayashi and S. Nakano, Chem, Pharm. Bull,, 29, Wisniewski, and T. Kindlik, Diss. Teodorescu, and E. Tudor, Revta Chim. Agrawal and E. Margoliash, Analvt. Sangadzhieva, K. Bagdasarov and P. Ivakhnenko, 1zv. Yamato and K. Kinoshita, Anal.
Sastry, B. Rao and K. Rao, Proc. A, 53, 7 Chem 56, Imondi, Int. Bando, T, Ogawa, H. Tsuji and K. Sasaoka, Clin. Chem, Winston-Salem, N. C , 36, Eisenwiener, F. Morger, W. Lergier and D. Gillessen, L Clin. Warren, 11, J. Avery and H. Malmstadt, Anal. Chem 54, Senthilnathan, S. Ramasamy and R. Hurtubise, Anal. Karnes, S. Schulman and J. Acta, , Karnes, R.
Bateh, J. Winefordner and S. Schulman, Clin. Winston-Salem N. Long, R. Norin and S. Su, Anal. Chughtai, Mikrochem. Burkina, I. Grindane and N. Guseva, Khim. Pormale, 1. Rosentals and N. Kashkina, Khim. Zh 10, Tomaszewska, Chem. Thielemann, Sci. Puzakov and F. Shemyakin, Farmatsiva [Moscow , 30, 41 Radulovic and Z. Blagojevic, Arh. Schwartz and J. Sherman, J. Mei, Yaowu Fenxi Zazhi, 3, Thielemann, Fresenius 2.
Cozzi, P. Desideri, L. Lepri and V. Coas, J. Gao, Yaowu Fenxi Zazhi, 3, 26 Cumpelik, Cosmet. Toiletries, 97, 67, 71 Wurst, M. Jurkova, Z. Zouchova and R. L, Chromatom. Harahap, R. Burford and J. Haken, J. Chromatoer,, , 53 Walters and N. Raghavan, J. Heard, jun, and G. Tritz, J. Takahashi, H. Shirono, N. Takai, A. Takeuchi and H. Funakubo, Seisan Kenkvu, 33, Demian and V.
Borbely, Rev. Ito, K. Maruta, Y. Imai, T. Kato, M. Ito, S. Nakajima, K. Fujita and T. Kurahashi, Clin. Berg, I. Chesner and N. Biochem,, 22, Gagliardi, A. Amato, A. Basili, G. Cavazzutti, and D. Tonelli, J. Abidi, J. Otto, and W. Harahap et a1 93 reported a gas-chromatographic method for the analysis of 4-aminobenzoic acid in the thermoplastic aromatic polyamides after alkali fusion.
The sample of the thermoplastic aromatic polyamide, containing equimolar ratios of 4-aminobenzoic acid and other acid was subjected to alkali fusion at ” for 2 hours with potassium hydroxide-sodium acetate 1.
The mixture was cooled and isophthalic acid was precipitated by adjusting the solution to pH 7. The precipitate was filtered off and isophthalic acid was derivatized to its dimethyl ester with methanolic BF, reagent. The remaining aqueous layer was adjusted to pH 6 and paminobenzoic and 3-aminobenzoic acid were extracted into chloroform and derivatized to their TMS derivatives.
Separation of the three derivatives was carried out on a column 12 ft X 0. The 3 and 4-aminobenzoic acids are separated on a. Randau and Schnell 95 have separated 4aminobenzoic acid on columns 25 cm X 1. The MP was superior, optimal separation occuring at ; on the M column, no separation was achieved at the lower temperature and only partial separation at 50 O.
It is concluded that the macroporous resins permit separation only achieved with the gel resins at much smaller particle size and greater column pressure, 5. Another method has also been published Standard solution containing 0.
PABA is used topically as a sunscreen agent usually in a concentration of. Its preparations are therefore effective in preventing sun burns but ineffecitve in preventing drug-relating or other photosensitive reactions associated with UVA light; combination with a benzophenone may give some added protection against such photosynthetic disorders.
Application of this solution once daily for 30 days did not give rise to cutaneous or systemic toxic symptoms. PABA has no protective effect when given by mouth. Some studies were reported on the improvement of the test specificity as well as comparison and combination with established or new tests Development of vitiligo in sunexposed areas following adminstration of aminobenzoic acid by mouth was reported 1 Precautions Aminobenzoate sunscreen agents should not be used by patients with previous experience of photosensitive or allergic reactions to chemically-related drugs such as sulfonamides, thiazide diuretics and certain local anesthetics, particularly benzocaine.
PABA is readily absorbed from the gastrointestinal tract after oral adminstration 2,3. The percutaneous absorption of PABA was determined in vitro through hairless guinea pig skin The absorption of PABA was greater through nonviable skin. Illel et. Using their skin model they compared the percutaneous absorption in appendage-free skin relative to normal skin.
The results confirmed that appendageal diffusion is the major bathway in hairless rat skin. In the absence of follides, the steady state flux and the amounts diffusing in one or two days are times lower than in normal skin. PABA serum and urine concentrations were measured in patients with normal, pathologic and pharmacologically inhibited pancreatic function A maximum increase of In patients with exocrine pancrease insufficiency or those with pharmacologically inhibited exocrine pancrease resulted in a significantly reduced PABAserum concentration.
Thyroid dysfunction was found to affect the small intestinal absorption of some drugs including p-aminobenzoic acid. Thus, examination of the effect in the i siru recirculating n perfusion and everted sac methods showed that the intestinal absorption of passively absorbed drugs were depressed in hyper- and hypothyroid rats Studies using the same above methods were undertaken by Miyagi et.
The transfer of p-acetamidobenzoic acid was not influenced by C o k When PABA was orally administered in the rat treated with Con A, the plasma concentrations of PABA and of acetamidobenzoic acid increased compared with control. No influence of Con A was observed in the I. The plasma concentrations of acetamidobenzoic acid was unchanged when this PABA metabolite was orally or I.
Branco and Torres determined the levels of some water-soluble vitamins in Planorbidae. The determinations were carried out in total snail and in digestive tract extracts of Biomphalaria glubrata.
While some vitamins like folk acid showed higher levels in the digestive tract extract than in the total snail extract, the concentration of other vitamins including PABA produced higher levels in the total snail extracts. Fendrich et. Greatest concentrations of PABA were noted in the kidneys, liver and intestines with almost none in the brain.
Koren et al. PABA distribution volume in CF patients was smaller, although not significantly so, than the controls. PABA is mainly metabolized in the liver 4 and kidney It is conjugated with glycine to form p-aminohippuric.
Small amounts of p-aminobenzoyl glucuronide, pacetamidobenzoyl glucuronide and traces of p-acetamidohippuric, p-acetamidobenzoic acid and unchanged aminobenzoic acid are also detected in urine 2, Chan et al.
PABA may be detected in urine as a metabolite of amethocaine, benzocaine and procaine 2. The metabolism of PABA is reported to be influenced by many factors. Acetyltransferase activities in the small intestinal mucosa and the liver were increased in rats treated with cancanavalin A These results suggest that concanavalin A will facilitate the metabolism of PABA in the small intestine and liver of rat.
The effect of ethanolamine on the acetylation of PABA was studied in adult rats The results showed that ethanolamine significantly increases the acetylation capacity of tissues.
Griffeth et. Moreover, the i vivo reaction of acetylation was n found to be significantly decreased by model trauma. This effect on in vivu pharmacokinetics appeared to be correlated closely with trauma’s influence on the conjugating enzymes and relatively independent of the post-traumatic response of the necessary co-substrates.
It is thus suggested that traumatic injury appears to have wide-ranging effects on a variety of determinants of hepatic drug metabolism. In an overview on renal disease and drug metabolism, Gibson reported that in a diseased kidney the metabolism of PABA, and other drugs known to be metabolized in the kidney, is reduced.
Renal disease, therefore, has its potential to alter not only the renal clearance of unchanged drug but also may substantially modify the metabolic transformation of drugs in both the liver and the kidney. The tissue distribution of acetyltransferase with PABA as a substrate in humans was investigated by Pacifici et.
All tissue specimens catalyse the acetylation of PABA at a significant rate. These results together with the detection of Nacetylating activity in the skin of other experimental animals and humans , suggest that the skin may play an important role in the metabolism of the drug and other armatic amines.
Relatively high levels of acetyl transferase activity was also found in urinary bladder cytosol of humans A number of other studies on the metabolic acetylation of PABA appeared in the literature. These include reports on the genetic control , kinetics , and inhibition studies of the acetyltransferase enzyme. Scheme 5 lists the major metabolites of PABA.
PABA is mainly excreted in urine as its conjugate, paminohippuric acid together with small amounts of paminobenzoyl glucuronide, p-acetamidobenzoyl glucuronide. Traces of p-acetamidohippuric acid, p-acetamidobenzoic acid and unchanged benzoic acid are also detected in urine 2. The PABA clearance was similar in the control 2.
Acknowledgements The authors would like to thank Mr. Tanvir A. Butt for typing this manuscript. Rizk, M. Walash and N. Rabou, Arch. Ed 6, 26 Radhakrishnamurty and G. Rao, J. India , 56, 79 Mynka and M. Lyutaya, Farm. Kiev , 4,38 Lai and R. Marsh, Acta Crystalloer. Killean, P.
Tollin, D. Watson and D. Young, W, 19, Anulewicz, G. Haefelinger, T. Krygowski, C. Regelmann and G. Ritter, Z. Inomata and T. Moriwaki, Nippon Kaeaku Zasshi, 9, Theoret, Spectrochim. Acta, Part A, 27, 11 Lauransan and J. Corset, Ann. Paris , 4, Churagov, D. Gambarov and Kh. Mamedov, Koord. Khim 17, Bromilov, R. Brownlee, D. Craik, P. Fiske, J. Rowe and M. Sadek, J. Perkin Trans. Sibi, E. Prince, J. LeMelle and R.
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Liu, F. Rusnak and M. Sakaitani, Chem. Nichols, A. Seibold and S. Doktor, J. Ye, J. Liu and C. Walsh, Proc. Keiner, R. Huettenrauch and A.
Eichhorn, Zentbl. Kumar and P. Indrasenan, J. Castellano, T. Medwick, J. Shinkai and L. Bailey, J Pharm. Arora, and C. Bhatnagar, Z. Albert, V.
Cimpu, M. Valeanu and El. Radulescu-Jercan, Rev. Roumaine Chem. Shukla, S. Ahmed and R. Dwivedi, Proc. India, Sect. A, 55, Jayaram and N. Gowda, Analyst, , El-Samman and D. Amin, Microchem. Delgado, Rev. Petrov, L. Karaseva and T. Bogoslovskaya, Zh. Zvesti 33, Laserna, E. Torres and J. Winefordner, Anal. Acta , Narayanan, J. Bello, D. Stokes and T. Vo-Dinh, Analusis, 19, Kurenman, F. Sheyanova and V. Boyarkina, Khim. Dam and L. Veinbergs, M. Pormale, N. Kashkina and E. Simsone, Latv. PSR Zinat.
Akad Vestis. Liu, Yaowu Fenxi Zazhi, 2, Bertini, V. Nuti and G. Linari, Bull. Zhang, Yaoxue Tongbao, 20, Wang and X. Li, Yaowu Fenxi Zazhi. Taniguchi, T. Yoshida, T. Kobayashi and S. Nakano, Chem, Pharm. Bull,, 29, Wisniewski, and T. Kindlik, Diss. Teodorescu, and E. Tudor, Revta Chim. Agrawal and E.
Margoliash, Analvt. Sangadzhieva, K. Bagdasarov and P. Ivakhnenko, 1zv. Yamato and K. Kinoshita, Anal. Sastry, B. Rao and K. Rao, Proc. A, 53, 7 Chem 56, Imondi, Int. Bando, T, Ogawa, H. Tsuji and K. Sasaoka, Clin. Chem, Winston-Salem, N. C , 36, Eisenwiener, F. Morger, W. Lergier and D. Gillessen, L Clin. Warren, 11, J. Avery and H. Malmstadt, Anal. Chem 54, Senthilnathan, S. Ramasamy and R. Hurtubise, Anal. Karnes, S. Schulman and J.
Acta, , Karnes, R. Bateh, J. Winefordner and S. Schulman, Clin. Winston-Salem N. Long, R. Norin and S. Su, Anal. Chughtai, Mikrochem. Burkina, I. Grindane and N. Guseva, Khim. Pormale, 1.
Rosentals and N. Kashkina, Khim. Zh 10, Tomaszewska, Chem. Thielemann, Sci. Puzakov and F. Shemyakin, Farmatsiva [Moscow , 30, 41 Radulovic and Z.
Blagojevic, Arh. Schwartz and J. Sherman, J. Mei, Yaowu Fenxi Zazhi, 3, Thielemann, Fresenius 2. Cozzi, P. Desideri, L. Lepri and V. Coas, J. Gao, Yaowu Fenxi Zazhi, 3, 26 Cumpelik, Cosmet. Toiletries, 97, 67, 71 Wurst, M. Jurkova, Z.
Zouchova and R. L, Chromatom. Harahap, R. Burford and J. Haken, J. Chromatoer,, , 53 Walters and N. Raghavan, J. Heard, jun, and G. Tritz, J. Takahashi, H. Shirono, N. Takai, A. Takeuchi and H. Funakubo, Seisan Kenkvu, 33, Demian and V. Borbely, Rev. Ito, K. Maruta, Y. Imai, T. Kato, M. Ito, S. Nakajima, K. Fujita and T. Kurahashi, Clin. Berg, I. Chesner and N. Biochem,, 22, Gagliardi, A. Amato, A. Basili, G. Cavazzutti, and D.
Tonelli, J. Abidi, J. Otto, and W. Wegscheider, J. Jin and H. Zhou, Yaowu Fenxi Zazhi, 6, 49 Willis and A. Kligman, k h s. Hoek, G. Sanders, A. Teunen and G. Tijtgat, Gut. Chesner, R. Allen-Narker, B.
Buckley and N. Lawson, Clin. Puntis, J. Berg, B. Buckley, I. Booth and A. McNeish, Arch. Bornschein, Z. Skopnik, J. Btendel-Ulrich and G. Heimann, Klin. Parrish et. Mathias et. Marmelzat and M. Ramport, Contact Dermatitis, 6, Horio and T. Higuchi, Dermatoloeica,, , Rossler, H. Janisch and K. Hampel, Gastroenterol.
Murata, K. Sasaki, N. Hikichi and H. Niwa, Ann. Tohoku Coll. Pharm,, 28, Miyagi;, N. Niwa, Yakuzaieaku, 45, Branco and I. Torres, Exp, Parasitol, 19, Fendrich, J. Kvetina, F. Deml and V. Grossmann, Sb. Ved, Pr.. Karlow Univ. Hradci Kralove, 11, Koren, Z. Weizmann, G. Forstner, S. McLeod and P.
Durie, Dif. Gibson, Am. Kidney Dis. Chan, J. Miners and D. Birkett, J. Tsuji, T. Orawa, N. Bando and K. Sasaoka, Biochem. Gasparyan, Tr. Griffeth, G. Rosen and E. Rauckman, Drug Metab. Pacifici, C. Bencini and A. Rane, Pharmacology, 32, Kawakubo, S.
Manabe, Y. Yamazoe, T. Nishikawa and R. Yerokun, W. Kirlin, A. Trinidad, R. Ferguson, F. Ogolla, A. Andres, P. Brady and D. Hein, Drug Metab. Glowinski and W. Weber, J. Hein, T. Smolen, R. Fox and W.
Weber, Pharm. Hein, A. Trinidad, T. Yerokun, R. Ferguson, W. Kirlin and W. Weber, Drup Metab. Trinidad, W. Kirlin, F. Andrews, T. Yeroku, R. Ferguson, P. Hein, ibid. Trinidad, D. Rustan, R. Ferguson, L. Miller, K. Bucher, W.
Ogolla and A. Andrews, Cancer Res, 50, Andrws, A. Ferguson, T. Yerokun, M. Mpezo and D. Grant, M. Blum, M. Beer and U. Meyer, Mol. Sasaki, S. Ohsako and T. Deguchi, J. Gollamudi, B. Muniraju and E. Schreiber, Enzyme, 25, Mattano and W.
Weber, Carcinogenesis, 8, Kilbane, T. Petroff and W. Hanria, R. Banks and V. Marhevka, Mol. Pharmacol, 21, Smith and P. Hanna, Biochem. Introduction 2. Description 2. I Nomenclature 2. Physical Properties 3. Stability 5. Synthesis 6. Methods of Analysis 6. Spectrophotometry 6. Fluorirnetry 6.
Ion Selective Electrode Method 6. Bumetanide fBMT is a potent loop diuretic similar to furosemide FRU in its pharmacological action but equally effective at one fortieth the dose on a weight basis. It is indicated for the treatment o edema associated with congestive heart failure, hepatic and renal f disease, including the nephrotic syndrome. Scored tablets of bumetanide, at potencies of 0. Bumetanide for injection, at a potency of 0.
Tablets of 0. Bumetanide is an odorless, white crystalline powder with a slightly bitter taste. Point The reported melting point range is “C. The lJSP recommends that bumetamide raw material be stored in air tight containers, and protected from light. The principal IJV absorption peaks of bumetanide in various solvents are listed in Table 11, and the E” values where available are given in parentheses.
The major observed bands have been correlated with the following functional groups:. The spectrum is shown in Figure 2 and the proton chemical shifts are assigned in Table 1V. The spectrum is shown in Figure 3, and the chemical shifts were assigned as listed in Table V.
The electron impact El mass spectrum of bumetanide is presented in Figure 4, with the spectrum being obtained on a HP MS system operating at an ionization potential of 70 eV. Bumetanide forms metal complexes with Cu lI , Mg l1. The site of complexation is believed to be between the carbonyl and the imino groups, with the complex being formed as a 1 : 1 metal-ligand species.
X-ray crystallographic information was obtained on a Scintag model XTS Powder patterns displaying d-spacings under the operating conditions listed below are given in Figure 5 , and the full data is collected in Table VII. S seconds 1.
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Watson and D. Young, W, 19, Anulewicz, G. Haefelinger, T. Krygowski, C. Regelmann and G. Ritter, Z. Inomata and T. Moriwaki, Nippon Kaeaku Zasshi, 9, Theoret, Spectrochim. Acta, Part A, 27, 11 Lauransan and J. Corset, Ann. Paris , 4, Churagov, D. Gambarov and Kh.
Mamedov, Koord. Khim 17, Bromilov, R. Brownlee, D. Craik, P. Fiske, J. Rowe and M. Sadek, J. Perkin Trans. Sibi, E. Prince, J. LeMelle and R. Lichter, Spectrosc. Registry of Mass Spectral Data, E. Stenhogen, S. Abrahamsson and F.
Mallonee, U. Hashimoto, J. Sunakoto and H. Fujii, Japan. Sakumoto, Bull. Walsh, M. Erion, A. Walts, J. Delany and G. Berchtold, Biochemistry, 26, McLeish, P. Wookey and K. Mortimer, Biochem. Kane and H. OBrien, J. Huang and F. Gibson, J. Kaplan and B. Nichols, J. Biol, , Goncharoff and B. Yanofsky, T. Platt, I.
Crawford, B. Nichols, G. Christie, H. Horowitz, M. VanCleemput and A. Wu, Nucleic Acids Res. Policastro, K. Au, C. Walsh and G. Berchtold, Am, Chem. Teng and B. Ganem, J. Teng, B.
Ganem, S. Doktor, B. Nichols, R. Bhatnagalr and L. Vining, J. Elkins and C. Ozebberger, T. Brickman and M. Mcintosh, Bacteriol. Liu, N. Quinn, G. Berchtold and C. Walsh, Biochernisa, 29, Walsh, J. Liu, F.
Rusnak and M. Sakaitani, Chem. Nichols, A. Seibold and S. Doktor, J. Ye, J. Liu and C. Walsh, Proc. Keiner, R. Huettenrauch and A. Eichhorn, Zentbl. Kumar and P. Indrasenan, J. Castellano, T. Medwick, J. Shinkai and L. Bailey, J Pharm. Arora, and C. Bhatnagar, Z. Albert, V. Cimpu, M. Valeanu and El. Radulescu-Jercan, Rev. Roumaine Chem. Shukla, S. Ahmed and R. Dwivedi, Proc. India, Sect. A, 55, Jayaram and N.
Gowda, Analyst, , El-Samman and D. Amin, Microchem. Delgado, Rev. Petrov, L. Karaseva and T. Bogoslovskaya, Zh. Zvesti 33, Laserna, E. Torres and J. Winefordner, Anal. Acta , Narayanan, J. Bello, D. Stokes and T. Vo-Dinh, Analusis, 19, Kurenman, F. Sheyanova and V. Boyarkina, Khim. Dam and L. Veinbergs, M. Pormale, N. Kashkina and E.
Simsone, Latv. PSR Zinat. Akad Vestis. Liu, Yaowu Fenxi Zazhi, 2, Bertini, V. Nuti and G. Linari, Bull. Zhang, Yaoxue Tongbao, 20, Wang and X. Li, Yaowu Fenxi Zazhi. Taniguchi, T.
Yoshida, T. Kobayashi and S. Nakano, Chem, Pharm. Bull,, 29, Wisniewski, and T. Kindlik, Diss. Teodorescu, and E. Tudor, Revta Chim. Agrawal and E. Margoliash, Analvt. Sangadzhieva, K. Bagdasarov and P. Ivakhnenko, 1zv. Yamato and K. Kinoshita, Anal. Sastry, B. Rao and K. Rao, Proc. A, 53, 7 Chem 56, Imondi, Int.
Bando, T, Ogawa, H. Tsuji and K. Sasaoka, Clin. Chem, Winston-Salem, N. C , 36, Eisenwiener, F. Morger, W. Lergier and D. Gillessen, L Clin.
Warren, 11, J. Avery and H. Malmstadt, Anal. Chem 54, Senthilnathan, S. Ramasamy and R. Hurtubise, Anal. Karnes, S. Schulman and J. Acta, , Karnes, R. Bateh, J. Winefordner and S. Schulman, Clin. Winston-Salem N. Long, R. Norin and S. Su, Anal. Chughtai, Mikrochem.
Burkina, I. Grindane and N. Guseva, Khim. Pormale, 1. Rosentals and N. Kashkina, Khim. Zh 10, Tomaszewska, Chem. Thielemann, Sci. Puzakov and F. Shemyakin, Farmatsiva [Moscow , 30, 41 Radulovic and Z. Blagojevic, Arh.
Schwartz and J. Sherman, J. Mei, Yaowu Fenxi Zazhi, 3, Thielemann, Fresenius 2. Cozzi, P. Desideri, L. Lepri and V. Coas, J. Gao, Yaowu Fenxi Zazhi, 3, 26 Cumpelik, Cosmet. Toiletries, 97, 67, 71 Wurst, M. Jurkova, Z. Zouchova and R. L, Chromatom. Harahap, R. Burford and J. Haken, J. Chromatoer,, , 53 Walters and N.
Raghavan, J. Heard, jun, and G. Tritz, J. Takahashi, H. Shirono, N. Takai, A. Takeuchi and H. Funakubo, Seisan Kenkvu, 33, Demian and V. Borbely, Rev. Ito, K. Maruta, Y. Imai, T. Kato, M. Ito, S. Nakajima, K. Fujita and T. Kurahashi, Clin. Berg, I. Chesner and N. Biochem,, 22, Gagliardi, A. Amato, A. Basili, G. Cavazzutti, and D.
Tonelli, J. Abidi, J. Otto, and W. Wegscheider, J. Jin and H. Zhou, Yaowu Fenxi Zazhi, 6, 49 Willis and A. Kligman, k h s. Hoek, G. Sanders, A. Teunen and G. Tijtgat, Gut.
Chesner, R. Allen-Narker, B. Buckley and N. Lawson, Clin. Puntis, J. Berg, B. Buckley, I. Booth and A. McNeish, Arch. Bornschein, Z. Skopnik, J. Btendel-Ulrich and G.
Heimann, Klin. Parrish et. Mathias et. Marmelzat and M. Ramport, Contact Dermatitis, 6, Horio and T. Higuchi, Dermatoloeica,, , Rossler, H. Janisch and K. Hampel, Gastroenterol. Murata, K. Sasaki, N.
Hikichi and H. Niwa, Ann. Tohoku Coll. Pharm,, 28, Miyagi;, N. Niwa, Yakuzaieaku, 45, Branco and I. Torres, Exp, Parasitol, 19, Fendrich, J. Kvetina, F. Deml and V. Grossmann, Sb. Ved, Pr.. Karlow Univ. Hradci Kralove, 11, Koren, Z.
Weizmann, G. Forstner, S. McLeod and P. Durie, Dif. Gibson, Am. Kidney Dis. Chan, J. Miners and D. Birkett, J. Tsuji, T. Orawa, N.
Bando and K. Sasaoka, Biochem. Gasparyan, Tr. Griffeth, G. Rosen and E. Rauckman, Drug Metab. Pacifici, C. Bencini and A. Rane, Pharmacology, 32, Kawakubo, S. Manabe, Y. Yamazoe, T. Nishikawa and R. Yerokun, W. Kirlin, A. Trinidad, R. Ferguson, F. Ogolla, A. Andres, P. Brady and D. Hein, Drug Metab. Glowinski and W. Weber, J. Hein, T. Smolen, R. Fox and W. Weber, Pharm. Hein, A. Trinidad, T. Yerokun, R. Ferguson, W. Kirlin and W.
Weber, Drup Metab. Trinidad, W. Kirlin, F. Andrews, T. Yeroku, R. Ferguson, P. Hein, ibid. Trinidad, D. Rustan, R. Ferguson, L. Miller, K. Bucher, W. Ogolla and A. Andrews, Cancer Res, 50, Andrws, A. Ferguson, T. Yerokun, M. Mpezo and D. Grant, M. Blum, M. Beer and U. Meyer, Mol. Sasaki, S. Ohsako and T. Deguchi, J. Gollamudi, B. Muniraju and E. Schreiber, Enzyme, 25, Mattano and W. Weber, Carcinogenesis, 8, Kilbane, T.
Petroff and W. Hanria, R. Banks and V. Marhevka, Mol. Pharmacol, 21, Smith and P. Hanna, Biochem. Introduction 2. Description 2. I Nomenclature 2. Physical Properties 3. Stability 5. Synthesis 6. Methods of Analysis 6. Spectrophotometry 6. Fluorirnetry 6. Ion Selective Electrode Method 6. Bumetanide fBMT is a potent loop diuretic similar to furosemide FRU in its pharmacological action but equally effective at one fortieth the dose on a weight basis.
It is indicated for the treatment o edema associated with congestive heart failure, hepatic and renal f disease, including the nephrotic syndrome. Scored tablets of bumetanide, at potencies of 0. Bumetanide for injection, at a potency of 0. Tablets of 0. Bumetanide is an odorless, white crystalline powder with a slightly bitter taste. Point The reported melting point range is “C. The lJSP recommends that bumetamide raw material be stored in air tight containers, and protected from light.
The principal IJV absorption peaks of bumetanide in various solvents are listed in Table 11, and the E” values where available are given in parentheses. The major observed bands have been correlated with the following functional groups:. The spectrum is shown in Figure 2 and the proton chemical shifts are assigned in Table 1V. The spectrum is shown in Figure 3, and the chemical shifts were assigned as listed in Table V.
The electron impact El mass spectrum of bumetanide is presented in Figure 4, with the spectrum being obtained on a HP MS system operating at an ionization potential of 70 eV. Bumetanide forms metal complexes with Cu lI , Mg l1.
The site of complexation is believed to be between the carbonyl and the imino groups, with the complex being formed as a 1 : 1 metal-ligand species.
X-ray crystallographic information was obtained on a Scintag model XTS Powder patterns displaying d-spacings under the operating conditions listed below are given in Figure 5 , and the full data is collected in Table VII.
S seconds 1. This process is analogous to the Hofmann-Martius reaction, but is conducted under less stringent conditions. This results in the formation of the debutylated amine and butyl chloride rather than in the rearrangement product commonly associated with this reaction when performed under pyrolysis conditions.
No other butylated compounds have been detected in samples stored under accelerated conditions for as long as 1 month at 55C. The synthetic route for bumetanide is shown in Figure 6. This is treated with ammonia to give 4-chloronitro-S- sulfamyl benzoic acid This is in turn is treated with a mixture of phenol and sodium benzoic acid in its bicarbonate to give 4-phenoxynitrosulfamyl sodium salt form IV ,which treated with hydrochloric acid gives 4-Phenuxymitrosulfamyl benzoic acid V.
The nitro group in V is reduced to an amino group by either treating with sodium acid. This compound is treated with either butyraldehyde or n-butanol and sulfuric acid to yield VII.
This product is then saponified by sodium hydroxide to yield the sodium salt of bumetanide VIII which is treated with hydrochloric acid to yield bumetanide BMT. Bumetanide responds to the following color tests: Koppanyi-Zwikker test Liebermanns test Mercurous Nitrate 6. USP specifies tests for the following related impurities of bumetanide: 3-Nitrophenoxy-S-sulfamoyl benzoic acid.
Butyl 3-butylaminophenoxysulfarnoyl benzoate. Bumetanide in alcohol is titrated with 0. The method uses electrogenerated C1- in a supporting electrolyte of 0. All the reported spectrophotometric methods are based on the UV absorption of bumetanide in 0. I N NaOH at nm. Patel et al. The method makes use of the absorption maximum a1 nm.
The low sensitivity can be attributed to the fact that the drug is diazotized without prior hydrolysis to liberate the primary amino group. Sastry et. The first method utilizef the formation of molybdenum blue when bumetanide was treated with Na,CO, and the Folin-Ciocalteu reagent. Bumetanide exhibits strong fluorescence in both alkaline and acidic media over the pH range of 3. It has an excitation maximum at nm and an emission maximum at nm.
In a 1M solution of glycine buffer at pH Bumetanide in 0. The detection limit is 0. Chao et al. RIA [14, Bumetanide was estimated either by quantifying precipitated antibody bound fractions [35], or by unbound fractions [ The RIA method uses 3H labelled bumetanide.
An immunogen consisting of 40 moles of N- 3-N-butyl amino-4phenoxysulfamoyl benzoyl glycine and one mole of bovine serum albumin was prepared and introduced into a rabbit. After sufficient time, the drawn serum was suitably harvested to obtain the antiserum. To generate the standard curve, 0. To each tube, 0. The ether phase was separated and evaporated to dryness. To the residue, 0. Then to each tube, 0.
The tubes were centrifuged at rpm at 2C for 30 minutes and either supernatant or bound portion were analyzed for radioactivity in a scintillator after adding one drop of concentrated H,SO, and 10 mL of toluene. A radiometric method for the determination of plasma levels of intact bumetanide in dogs when given both by oral and intravenous routes has been reported. Halladay et al.
A system comprising of Whatman filter paper no. I , borate buffer at pH 9. For estimation of bumetanide in biological fluids, various workers extracted the drug with either ether or ethyl acetate after the samples were acidified with various agents. A more specific solid phase extraction procedure was reported by Ameer et al. The procedure uses a SepPak disposable column containing ODS bonded phase, and the loaded sample containing 4-Benzyl bumetanide the internal standard was eluted with methanol.
The eluent was analyzed by HPLC. A Schleicher and Schill paper No. Bumetanide was detected by its intrinsic fluorescence at nm, at a R, of 0. Similarly Pentikainen et al. In this method, detection was performed either by UV or radioactivity. The method uses a plate coated with silica gel GF2C4. The method allows the determination of diuretics in the range of I – 10 gg.
HPLC methods play an important role in the determination of bumetanide due to the low therapeutic dose levels used. In most cases, the samples are subjected to one of the preliminary clean up procedures discussed in 6. Phaphate Buffer Detector Referena 8. UV detn 0. Phaspbre Buffer of pH3. Berthod et al. This method utilized Nucleosil C,8 columns, and a n-BuOH sodium dodecyl sulfate mixture as the mobile phase. In a similar way, Sentell et al. This methods is rapid since it allows the direct injection of physiological fluids, avoiding details of sample preparation.
Bumetanide can be determined by gas chromatography in physiological fluids or in dosage forms. In most cases, the samples were derivitized and extracted from the biological matrix. Fagurlund et al.
The injector and detector temperatures were ” and “, respectively. Lisi et al. The samples were alkylated and analyzed on a column packed with a fused silica coated with HP Ultra. Hydrogen was used as the carrier gas, and the injector and detector temperatures were maintained at C and C respectively. Feit et al. GLC was performed on a column packed with 1. The injection port, column, and detector were maintained at “, ,” and C.
Davies et al. The temperatures of the injection port, detector, and column were “C, “C, and C respectively. Hioki et a]. A method was reported by Yoon et al. In dogs, bumetanide is excreted unchanged, whereas in humans and rats, almost complete biotransformation is observed to either urinary or fecal metabolites. The structures of bumetanide and its metabolites are given below.
Desbutyl bumetanide V is common to all species, and the metabolites are relatively inactive. Maximum daily dose 10 inglday. Pharmacodynamicq: Onset of action Peak effect Duration of effect iv within mins. Practical considerations: No dosing adjustments are needed in renal failure, although the compound should be used with caution in patients with renal dysfunction to minimize alteration in electrolyte balance.
No dosing changes are needed for patients with congestive heart failure. Bumetanide should be used with caution in combination with other Otto-toxic agents. Asbury M. Bourke E.. To an ice-cold solution 5 ml of 4-aminobenzoic acid in 0. The fluorescence was measured at nm excitation at nm.
Samples and solutions containing 0. Their extinctions were determined in a Pulfrich photometer using an S filter. A curve of extinction values versus the content of the drug was given.
The detection of a mixture of p-aminobenzoic acid and procainamide is also reported The drug was photocolorimetrically determined 64 using its color reaction in acid media with glutaconaldehyde, the product of the alkaline decomposition of Npyridylpyridinuim chloride-HC1.
Thirty minutes later, the absorbance was measured at nm. The drug was also determined 65 by diazotisation with 2N-HCl 0. The optimum pH for maximum color development is in the range of 7 to The extinction of the solution was measured at nm. The calibration graph was rectilinear in the range of 0. The absorbance of the dye was measured at nm A photometric determination of 4-aminobenzoic acid was reported To 1 ml of solution containing 10 mg of the drug were added 5 ml of M-HCl and 1 ml of 0.
After 2 minutes, 2 ml of 0. After further 3 minutes, the solution is diluted to 50 ml with water and the extinction is measured at nm. An assay for the measurement of urinary 4-aminobenzoic acid in the oral pancreatic-function test was reported The measurement of the acid in urine after oral acid administration of N-benzoyl-L-tyrosylaminobenzoic has been studied with 4-dimethylaminocinnamaldehyde as chromogenic reagent.
The latter reacts with 4-aminobenzoic acid in acidic solution pH 1. The calibration graph is rectilinear for up to pg m1-I of p-aminobenzoic acid in the sample.
Several colorimetric and fluorometric methods were described for the quantitation of primary arylamines These include: formation of N-substituted derivatives of p 1 nitrophenylazobenzamide. Condensation with glutaconic dialdehyde to yield 3 colored Schiff’s base.
Bratton-Marshall method for urinary 4-aminobenzoic acid have been evaluated Urine samples are hydrolysed with HC1 for. Portion of the hydrolysate are diluted to 5 ml and treated with 0. The calibration graph is rectilinear for 0. The method was intended as a test for excocrine pancreatic function after administration of bentiromide.
Bando et a1 71 have reported an enzymic method for selective determination of 4-aminobenzoic acid in urine. Urine 1 ml was heated at loo0 for 2 hours with 4M-KOH, then mixed with anhydrous acetic acid and incubated at for 20 minutes with 4-aminobenzoate hydroxylase 50 miu.
After addition of g 1-‘ trichloroacetic acid, 0. A colorimetric determination of 4-aminobenzoic acid and other primary aromatic amines using N-alkyl aminophenol and iodine has also been reported The determination of urinary 4-aminobenzoic acid with fluorescamine in the pancreatic function test with bentiromide have been published An experimental procedure is described 75 whereby addition of poly acry1ic acid to solution of 4-aminobenzoic.
NH, : H,O Solvent System Cyclohexane: ethyl acetate: chloroform: acetone Cyclohexane: ethylacetate: methanol Cyclohexane: ethylacetate: chloroform and Alkaline or neutral solvent systems w m. Karnes et a1 76 reported a comparative evaluation of two substrates for urinary determination of 4-aminobenzoic acid by room-temperature phosphorimetry.
The substrates considered were: i filter paper S. In each instance, calibration graphs were rectilinear in the range 0 to 40 mg I-‘ of 4-aminobenzoic acid. Karnes et a1 77 have also determined 4-aminobenzoic acid in urine by room-temperature phosphometry, with application to the bentiromide test for pancreatic function.
The drug was derivatized with fluorescamine. The optimum pH, buffer concentration and phosphorescence characteristics are discussed. Table 10 summarizes the several thin-layer chromatographic methods reported on p-aminobenzoic acid Two more TLC methods have also been reported 89, Cumpelik 9 1 described a gas liquid chromatographic system for analysis of p-aminobenzoic acid and other multiple absorber sunscreens.
The gas chromatographic retention times of different UV absorbing agents used in sunscreen preparations are compiled as an aid to identification in cosmetic samples. The temperature was programmed from to at. Table High performance liquid chromatography of p-aminobenzoic acid Support and column pBondapak C,, Mobile phase Flow rate 1.
All the samples were silanized and centrifuged. Wurst et a 92 developed a gas-chromatographic 1 method for determining trimethylsilyl derivatives of 4aminobenzoic acid and other carboxylic acid in mixtures of biological materials. The separation was performed on 1,5-bis m-phenoxypheny1 – 1,1,3,3,5,5-hexaphenyltrisiloxane as stationary phase. Its efficiency was compared with that of SE Nitrogen carrier gas, flame ionisation detection, and a temperature programming mode were used.
Harahap et a1 93 reported a gas-chromatographic method for the analysis of 4-aminobenzoic acid in the thermoplastic aromatic polyamides after alkali fusion. The sample of the thermoplastic aromatic polyamide, containing equimolar ratios of 4-aminobenzoic acid and other acid was subjected to alkali fusion at ” for 2 hours with potassium hydroxide-sodium acetate 1. The mixture was cooled and isophthalic acid was precipitated by adjusting the solution to pH 7. The precipitate was filtered off and isophthalic acid was derivatized to its dimethyl ester with methanolic BF, reagent.
The remaining aqueous layer was adjusted to pH 6 and paminobenzoic and 3-aminobenzoic acid were extracted into chloroform and derivatized to their TMS derivatives.
Separation of the three derivatives was carried out on a column 12 ft X 0. The 3 and 4-aminobenzoic acids are separated on a. Randau and Schnell 95 have separated 4aminobenzoic acid on columns 25 cm X 1. The MP was superior, optimal separation occuring at ; on the M column, no separation was achieved at the lower temperature and only partial separation at 50 O.
It is concluded that the macroporous resins permit separation only achieved with the gel resins at much smaller particle size and greater column pressure, 5. Another method has also been published Standard solution containing 0. PABA is used topically as a sunscreen agent usually in a concentration of.
Its preparations are therefore effective in preventing sun burns but ineffecitve in preventing drug-relating or other photosensitive reactions associated with UVA light; combination with a benzophenone may give some added protection against such photosynthetic disorders.
Application of this solution once daily for 30 days did not give rise to cutaneous or systemic toxic symptoms. PABA has no protective effect when given by mouth. Some studies were reported on the improvement of the test specificity as well as comparison and combination with established or new tests Development of vitiligo in sunexposed areas following adminstration of aminobenzoic acid by mouth was reported 1 Precautions Aminobenzoate sunscreen agents should not be used by patients with previous experience of photosensitive or allergic reactions to chemically-related drugs such as sulfonamides, thiazide diuretics and certain local anesthetics, particularly benzocaine.
PABA is readily absorbed from the gastrointestinal tract after oral adminstration 2,3. The percutaneous absorption of PABA was determined in vitro through hairless guinea pig skin The absorption of PABA was greater through nonviable skin. Illel et. Using their skin model they compared the percutaneous absorption in appendage-free skin relative to normal skin.
The results confirmed that appendageal diffusion is the major bathway in hairless rat skin. In the absence of follides, the steady state flux and the amounts diffusing in one or two days are times lower than in normal skin. PABA serum and urine concentrations were measured in patients with normal, pathologic and pharmacologically inhibited pancreatic function A maximum increase of In patients with exocrine pancrease insufficiency or those with pharmacologically inhibited exocrine pancrease resulted in a significantly reduced PABAserum concentration.
Thyroid dysfunction was found to affect the small intestinal absorption of some drugs including p-aminobenzoic acid. Thus, examination of the effect in the i siru recirculating n perfusion and everted sac methods showed that the intestinal absorption of passively absorbed drugs were depressed in hyper- and hypothyroid rats Studies using the same above methods were undertaken by Miyagi et.
The transfer of p-acetamidobenzoic acid was not influenced by C o k When PABA was orally administered in the rat treated with Con A, the plasma concentrations of PABA and of acetamidobenzoic acid increased compared with control. No influence of Con A was observed in the I.
The plasma concentrations of acetamidobenzoic acid was unchanged when this PABA metabolite was orally or I. Branco and Torres determined the levels of some water-soluble vitamins in Planorbidae. The determinations were carried out in total snail and in digestive tract extracts of Biomphalaria glubrata. While some vitamins like folk acid showed higher levels in the digestive tract extract than in the total snail extract, the concentration of other vitamins including PABA produced higher levels in the total snail extracts.
Fendrich et. Greatest concentrations of PABA were noted in the kidneys, liver and intestines with almost none in the brain. Koren et al. PABA distribution volume in CF patients was smaller, although not significantly so, than the controls. PABA is mainly metabolized in the liver 4 and kidney It is conjugated with glycine to form p-aminohippuric.
Small amounts of p-aminobenzoyl glucuronide, pacetamidobenzoyl glucuronide and traces of p-acetamidohippuric, p-acetamidobenzoic acid and unchanged aminobenzoic acid are also detected in urine 2, Chan et al.
PABA may be detected in urine as a metabolite of amethocaine, benzocaine and procaine 2. The metabolism of PABA is reported to be influenced by many factors. Acetyltransferase activities in the small intestinal mucosa and the liver were increased in rats treated with cancanavalin A These results suggest that concanavalin A will facilitate the metabolism of PABA in the small intestine and liver of rat.
The effect of ethanolamine on the acetylation of PABA was studied in adult rats The results showed that ethanolamine significantly increases the acetylation capacity of tissues. Griffeth et. Moreover, the i vivo reaction of acetylation was n found to be significantly decreased by model trauma.
This effect on in vivu pharmacokinetics appeared to be correlated closely with trauma’s influence on the conjugating enzymes and relatively independent of the post-traumatic response of the necessary co-substrates. It is thus suggested that traumatic injury appears to have wide-ranging effects on a variety of determinants of hepatic drug metabolism. In an overview on renal disease and drug metabolism, Gibson reported that in a diseased kidney the metabolism of PABA, and other drugs known to be metabolized in the kidney, is reduced.
Renal disease, therefore, has its potential to alter not only the renal clearance of unchanged drug but also may substantially modify the metabolic transformation of drugs in both the liver and the kidney.
The tissue distribution of acetyltransferase with PABA as a substrate in humans was investigated by Pacifici et. All tissue specimens catalyse the acetylation of PABA at a significant rate.
These results together with the detection of Nacetylating activity in the skin of other experimental animals and humans , suggest that the skin may play an important role in the metabolism of the drug and other armatic amines.
Relatively high levels of acetyl transferase activity was also found in urinary bladder cytosol of humans A number of other studies on the metabolic acetylation of PABA appeared in the literature. These include reports on the genetic control , kinetics , and inhibition studies of the acetyltransferase enzyme.
Scheme 5 lists the major metabolites of PABA. PABA is mainly excreted in urine as its conjugate, paminohippuric acid together with small amounts of paminobenzoyl glucuronide, p-acetamidobenzoyl glucuronide. Traces of p-acetamidohippuric acid, p-acetamidobenzoic acid and unchanged benzoic acid are also detected in urine 2.
The PABA clearance was similar in the control 2. Acknowledgements The authors would like to thank Mr. Tanvir A. Butt for typing this manuscript. Rizk, M. Walash and N.
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