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In the late nineteenth and early twentieth centuries, British physicians led the way in tropical medicine research. Several years later scientific advances had slowed, and Fairley's numerous contributions were thus most welcome. Neil Hamilton Fairley was born of Scottish parents at Victoria, Australia. After qualification at Melbourne, he joined the Australian Army Medical Service (AAMS) and after several minor research projects, made valuable contributions to the understanding of tropical sprue at Bombay ( now Mumbai), India. However, Fairley's major researches were carried out during World War II (1939–45). Together with J S K Boyd he demonstrated the great value of sulphaguanidine in bacillary dysentery. Working in northern Australia and the south-Pacific region, he both contributed to elucidation of the Plasmodium vivax life-cycle, and more importantly demonstrated the value of alternative anti-malarial compounds to quinine (which was not readily available). Back in London after the war, Fairley briefly occupied the Wellcome Chair of Tropical Medicine, strongly supported London's clinical tropical medicine, and was subsequently knighted in 1950.

The viability of the tandem photochemical reaction-chemiluminescence detection has been studied for an heterogeneous group of sulphonamides (sulphamethoxazole, sulphadiazine, sulphamerazine, sulphamethoxypyridazine, sulphacetamide, sulphadimidine, sulphanilamide, sulphathiazole and sulphaguanidine) using sulphamethoxazole (whose chemiluminescent behaviour has not been previously reported) as a test substance. The ‘on-line’ photochemical-reaction of sulphonamides provides an enhancing influence on the chemiluminometric response of the drugs during their oxidation by potassium permanganate in sulphuric acid medium (sulphamethoxazole, sulphacetamide, sulphadimidine and sulphanilamide increase their chemiluminometric response by a factor≥10). The determination is performed in a FI-assembly by using a photoreactor consisting of a 670 cm×0.5 mm i.d. long piece of PTFE tubing coiled around a 8 W low-pressure mercury lamp. Linear calibration graphs were obtained over a concentration range of 2–3 orders of magnitude, typically in the range ≈0.06–8 μg ml−1 (sulphamethoxazole, sulphacetamide, sulphadimidine, sulphanilamide, sulphathiazole, sulphaguanidine); and in the range ≈0.08–100 μg ml−1 (sulphadiazine, sulphamerazine and sulphamethoxypyridazine). Limits of detection were between 30 μg l−1 (for sulphanilamide) and 80 μg l−1 (for sulphadiazine, sulphamethoxypyridazine, sulphadimidine and sulphaguanidine). The sample throughput was 60 h−1 in all cases. The assessment of the photodegradation step on the molecular structure of sulfonamides was established by recording UV and fluorimetric spectra. The viability of an on-line photochemical reaction-fluorimetric determination of sulphathiazole and sulphadimidine was confirmed. The method was also applied to the determination of dissolution profiles of commercially available formulations of solid oral administration of sulfamethoxazole. The empirical profiles were adjusted by regression using the three-parameters plot method.

Two electrically neutral analytes previously observed to be separated from the neutral marker in capillary zone electrophoresis (CZE) experiments [sulphanilamide (SAA) and sulphaguanidine (SGW)] have been examined to determine the basis for separation. The degree of separation increases markedly with buffer concentration and improves with increasing field strength. On the basis of the apparent electrophoretic mobilities in conventional CZE, migration times in a zero EOF environment were calculated for SAA, SGW and six other sulphonamides that were known to be ionized. These six markers were used to test the legitimacy of our predictions and to correct for small discrepancies between the predicted and observed migration times. It was concluded that SAA and SGW have negligible electrophoretic mobilities and that they are retained in the electrical double layer close to the capillary wall. A mechanism for adsorption is proposed and the generality of the phenomenon is discussed.

Hydrolysis is one of the most common reactions controlling abiotic degradation and is one of the main paths by which substances are degraded in the environment. Nevertheless, the available information on this process for many compounds, including sulphonamides (a group of antibiotic drugs widely used in veterinary medicine), is very limited. This is the first study investigating the hydrolytic stabilities of 12 sulphonamides, which were determined according to OECD guideline 111 (1st category reliability data on the basis of regulatory demands on data quality for the environmental risk assessment of pharmaceuticals). Hydrolysis behaviour was examined at pH values normally found in the environment. This was prefaced by a discussion of the acid-base properties of sulphonamides. All the sulphonamides tested were hydrolytically stable at pH 9.0, nine (apart from sulphadiazine, sulphachloropyridazine and sulphamethoxypyridazine) were stable in this respect at pH 7.0 and two (sulphadiazine and sulphaguanidine) at pH 4.0 (hydrolysis rate≤10%; t(0.5 (25°C))>1 year). The degradation products were identified, indicating two independent mechanisms of this process. Our results show that under typical environmental conditions (pH and temperature) sulphonamides are hydrolytically stable with a long half-life; they thus contribute to the on-going assessment of their environmental fate.

A rapid, simple and sensitive spectrophotometric method for the determination of some sulphanilamides is described. The method is based on the formation of blue coloured disazo dyes by the diazotization of sulphonamides viz. sulphanilamide (SA), sulphamerazine (SMR), sulphamethazine (SMZ), sulphadimethoxine (SDM), sulphamethoxazole (SMX), sulphadiazine (SDA), sulfathiazole (STZ), sulphaguanidine (SGN), sulphamonomethoxine (SMM), sulphamethoxypyridazine (SMP) in 0.5M hydrochloric acid media at ice bath followed by the azocoupling reaction with acid monoazo dye Tropaeolin O (TrO) at pH=10.5. Formed products are stable for 10h at room temperature. Effective molar absorptivities at absorbance maxima 595nm for disazo dyes were ∼10(4)M(-1)cm(-1). Stoichiometric ratios of the components of disazo dyes were determined by means of mole ratio and continuous variations methods. Linear ranges for sulphanilamides determination were 0.4-14.0μgml(-1). The methods were successfully approved at suphanilamides determination in model solutions and commercial pharmaceutical preparations.

A flow-injection method with photochemically induced fluorescence (PF) or native fluorescence (NF) detection was developed for the determination of four sulphonamides. Sulphamethazine was determined using PF and sulphanilamide, sulphaguanidine and sulphacetamide using NF. Linear calibration graphs were obtained over a concentration range of one order of magnitude. The relative standard deviations were within the range 0.4–5%. Limits of detection were between 0.015 and 0.12 μg ml−1. The method was applied to the determination of sulphonamides in milk and pharmaceutical preparations.

The inclusion complex of sulphaguanidine (SGN) in β-cyclodextrin has been investigated. To avoid the problem of the low solubility of β-cyclodextrin in water, solutions of β-cyclodextrin in urea have been used. A 1:1 stoichiometry and an association constant of 450 M−1 have been established for the complex. A new spectrofluorimetric method has been developed for the determination of SGN residues in honey samples. This sulphonamide is widely employed for honey treatment. The method for the determination is based on second-order multivariate calibration, applying parallel factor analysis (PARAFAC). No previous separation or samples pre-treatment were required. The calibration solutions were prepared in water, with concentrations in the range from 0.02 to 0.20 μg mL−1 for SGN. The use of the second-order calibration method in the standard addition mode, using the excitation–emission matrices (EEMs) as analytical signal, allowed its determination in honey samples, even in the presence of interferences, with satisfactory results. The proposed procedure was validated by comparing the obtained results with a HPLC method, with satisfactory results for the assayed method.

The host-guest inclusion complexes of sulphamethoxazole (SMTX) and sulphaguanidine (SGN) with beta-cyclodextrin, in aqueous solutions, have been investigated. A 1:1 stoichiometry of the complexes was established, the association constants were calculated by different methods, and the influence of several chemical variables on the complexation processes were established. According to the results obtained, a spectrofluorimetric method for the determination of these sulphonamides has been proposed. The individual and binary mixtures of both sulphonamides have been determined in human urine samples, at representative therapeutic ranges, by application of a first-order multivariate calibration partial least squares (PLS-1) model. The calibration set was designed with 9 samples, containing different concentrations of the two sulphonamides, and 8 blank urine samples, with the aim of modelling the variability of the background. The concentration ranges for the sulphonamides were up to 0.5 microg mL(-1) for SMTX and 1.0 microg mL(-1) for SGN. Figures of merit as selectivity, analytical sensitivity and limit of detection (LOD) were also calculated. The proposed procedure was validated by comparing the obtained results with a HPLC method, with satisfactory results for the assayed method.

I would like to add a personal anecdote to Scadding's article1 on bacillary dysentery in Egypt. In March 1944 I was admitted to hospital in Bangalore, India, with mild bacillary dysentery. My treatment consisted of repeated doses of a mixture of magnesium and sodium sulphate, the standard treatment at that time. It seemed to me that this purgation was perpetuating my original symptoms and that this might go on indefinitely. I therefore hatched a plot with the Italian orderly (Italian prisoners of war were employed as orderlies in hospitals in India) to chart my treatment but not to give it to me. The result was impressive; within 48 hours I was ‘formed’, and was discharged. Scadding referred briefly to ‘Some probably harmful procedures were still sometimes advocated; for instance there was even the residue of the idea that saline purgation ought to be helpful in ridding the bowel of the infective agent.’ Exactly when sulphaguanide became available in India and South East Asia is not clear, but it was certainly in use in Singapore in September 1945. Stitt's Diagnosis, Prevention and Treatment of Tropical Diseases,2 published in 1943, clarifies the situation; after quoting a number of favourable trials of sulphaguanidine, it states, ‘A large supply of this drug has been very recently sent from the United States to Cairo for the use of the British armies in the Near East and Africa’—but not to India, apparently. One wonders how many military man-hours were wasted by this useless purgative treatment.

Isoflavones in alkaline dimethylsulphoxide at 100° under a nitrogen atmosphere reacted with sulphaguanidine to give phenolic sulphonamidopyrimidines.

1. Pulmonary absorption half-times (min) in the rat for four sulphonamides and three antitubercular drugs were: sulphadimethoxine

The 1,3-dipolar cycloaddition reaction of arylsulphonyl azides to 1,3-disubstituted-1,4-dihydropyridines afforded 2,7-diazabieyclo {4.1.0} hept-3-ene derivatives (III).These compounds exhibited more significant analgesic and anticoccidial activities than aspirin and sulphaguanidine respectively.

The coordination behaviour of azomethines derived from salicylaldehyde and some well known sulpha drugs, viz. sulphathiazole, sulphisoxazole, sulphaphenazole, sulphapyridine, sulphadiazine and sulphaguanidine has been systematically studied. The resulting complexes have been subjected to elemental analyses, conductance measurements, molecular weight determination and electronic infrared and proton nuclear magnetic resonance spectral studies and their plausible structures have been discussed.

Studies were made of copper electrodeposited onto a (111) plane of a copper single crystal from an acidic CuSO4 bath containing various concentrations of sulphanilamide. As the concentration of sulphanilamide is increased the pyramidal type of growth deposited from the pure bath changes to a layer deposit which transforms to ridges and then becomes polycrystalline at all current densities. The critical concentrations of sulphanilamide for the transitions depend on the current density.

Studies have been made of copper electrodeposited onto a (110) face of copper from a highly purified solution of copper sulphate containing known concentrations of sulphaguanidine. At very low concentrations of sulphaguanidine larger ridges with occasional pyramids were observed, at intermediate concentrations the ridges were smaller, and at higher concentrations polycrystalline deposits were found. The change in the growth habit of the deposit depends on the current density and the concentration of addition agent, and it is explained using complexation theory.

The effects of separately varying the packing fraction (P), the nature (N) and concentration (C) of disintegrants on both the tensile strength and disintegration times of sulphaguanidine tablets are in the orders, respectively, of P >N >N and N >P >N. The combined effects of these variables on the tensile strength are found to be very close to zero and are in the order of N&C > P&N > P&C while those for the disintegration times are significantly removed from zero and the order is P&N > P&C > N&C . Thus, the results indicate that the type and relative proportions of the disintegrants in the formulation have a more complex effect on the disintegration time of the tablets than on their tensile strengths. The ranking of the effects of the various disintegrants on disintegration times is potato starch > alginic acid > methylcellulose.

The results on the studies of various thermodynamic parameters for the oxidation of seven sulpha drugs, viz. sulphanilamide, sulphacetamide(s), sulphasomidine, sulphaguanidine, sulphadiazine, sulphapyridine and sulphamethizole, by the peroxydisulphate ion are reported and discussed. All the reactions under study obeyed the Arrhenius equation. The validity of the isokinetic relationship and other related equations have been tested. An attempt has been made to correlate these findings with the mechanism operative in the oxidation of sulpha drugs by the peroxydisulphate ion.

The sulphaguanidine complexes of Fe(II), Cu(II), Cd(II), V(IV), Pb(II), Se(IV), Sn(IV) and Mo(VI) were prepared and were characterized by elemental analysis, and UV and i.r. spectroscopy. The stoichiometry for Fe(II) and Cu(II) was 1:2 (metal : sulphaguanidine) and 1:1 for other metal ions. Stability constants for aqueous solution of these complexes have been determined.

Equimolar reactions of Bu2SnO and Ph2SnO with azomethines derived by the condensation of salicyladehyde with some well known sulphadrugsviz. sulphathiazole, sulphaphenazole, sulphadiazine, sulphaguanidine and 2-(p-aminobenzene sulphonamido)-4,5-dimethyl oxazole yield a new series of organotin(IV) complexes. The infrared and proton magnetic resonance spectral studies indicate coordination of phenolic oxygen and azomethine and secondary amino nitrogens providing a five coordinated environment at the tin atom.

Various thermodynamic parameters, namely energy of activation Ea, enthalpy of activation ΔH‡, free energy of activation ΔF‡, entropy of activation ΔS‡ and frequency factor A, for the oxidation of sulphanilamide, sulphacetamide, sulphadiazine, sulphaguanidine and sulphamethizole by periodate are reported and their role in the mechanism is discussed. All the reactions obeyed the Arrhenius equation, plots of log k against 1/T being linear. The validity of the isokinetic relationship and other related equations have been tested. An attempt has been made to correlate these findings with the nature of the transition state formed in the oxidation of sulpha drugs by periodate.

The voltammetric behaviour of sulphanilic acid and eight sulphonamides at the glassy carbon electrode is discussed. These compounds were found to undergo a 2e− process which appeared to involve the formation of iminobenzoquinone as the final product. The pKa values relating to the deprotonation of the p-amino substituent on the phenyl ring, evaluated from the voltammetric data, were found to be in good agreement with those obtained from ultraviolet spectroscopic data. Voltammetric methods were applied to the analysis of selected mixtures, to the determination of sulphaguanidine in a drug formulation, and as a method for the detection of sulphonamides after high-performance liquid chromatography.

Influence of five sulpha drugs,viz., Sulphanilamide, Sulphadiazine, Sulphaguanidine, Sulphamerazine, and Sulphathiazol has been studied under pot culture conditions. Variations in growth exposition as influenced by these have been described with a critical discussion in the context of the latest available literature on the mechanism of these drugs. Further possible lines of work have been put forward.

A hypermelanotic rash is described in 160 Bantu patients undergoing sulphone treatment for leprosy in the Belgian Congo. A similar rash has been observed in a patient taking sulphaguanidine, and in another taking sulphathiazol. The histology of the lesions is described, and the mechanism of their production is discussed.

Some fifty isolates of moulds, mainly Aspergillus spp. and Penicillium spp., were tested for their reaction to sulphanilamide, sulphonamide E.O.S., sulphapyridine, sulphamezathine, sulphaguanidine, propamidine and phenamidine. The moulds showed a high degree of specificity in their reaction to the drug concentrations: Aspergillus spp. were more susceptible to the drugs than were Penicillium spp. Most of the species included in the Aspergillus glaucus group were inhibited by concentrations of 1/8000 (125 p.p.m.) of sulphanilamide, sulphonamide E.O.S. or propamidine. Similar concentrations of sulphapyridine, sulphamezathine, sulphaguanidine and phenamidine had only a slight inhibitory effect on mould development. A. versicolor and A. sydowi showed very similar reactions to the drug concentrations, which is in keeping with their relationship on morphological grounds. In general, Penicillium spp. were not affected by small concentrations (1/2000 or less) of the drugs and were only partially inhibited by higher concentrations (up to 1/125) of sulphonamide E.O.S. Propamidine was more effective against certain Penicillium spp. though not all were susceptible. Some of the moulds were slightly stimulated by small concentrations of the drugs. No difference in the fungistatic effect of sulphonamide E.O.S. was apparent at different pH levels between 4 and 8. Different strains of the same species sometimes showed different degrees of resistance or susceptibility to the drug concentrations. This was particularly noted for strains of Aspergillus ruber, two of which showed marked resistance to propamidine when incorporated in beer-wort agar while four other strains of the same species were susceptible to the drug when incorporated in this medium. The two resistant strains, however, were susceptible to propamidine when incorporated in the synthetic Czapek-Dox medium. 4 p.p.m. of p-aminobenzoic acid was found to annul the fungistatic action of sulphonamide E.O.S. at concentrations of 250 p.p.m. The addition of p-aminobenzoic acid to a synthetic medium incorporating propamidine did not annul the inhibitory action of this drug.

The i.r. absorption spectra of enantiotropic crystal modifications of sulphonamides show regular shifts of the aniline-NH 2 -frequencies which allow conclusions to the conditions of stability. The modification stable at room temperature absorbs at lower frequencies than the unstable one because of stronger H-bonds. In the case of enantiotropy it is the lower melting modification and in the case of monotropy it is the higher melting form. The shifts of the SO 2 -NH-frequencies show no regularity. Two modifications of sulphanilamide, sulphathiazole, sulphaxylamide, sulphaguanidine, sulphathiourea and mafenide hydrochloride were investigated. The spectra of sulphathiazole I and II are especially remarkable so far as mod. I (m.p. 202°) has no SO 2 -NH-frequency while mod. II shows this band. Amide-imide-tautomerization is suggested to cause the polymorphism of this both modifications. The modification stable at room temperature therefore has amide-structure while to the high temperature form imide-structure is ascribed.

Cyclocondensation of sulphaguanidine acetate with chalcones in dimethylsulphoxide at 110° gave 4,6-diphenylsulphapyrimidine acetates.

Two titrimetric methods using N-bromophthalimide (NBP) and N-bromosaccharin (NBSA) have been developed for the determination of some sulpha drugs such as Antrima, Elkosin, Las, Madribon, Orisul, Septran, sulphaguanidine, Urolucosil and two laboratory-made tablets of pure sulphaguanidine and pure sulphacetamide. In these methods the sulphonamides present in the drugs are determined via bromination using NBP or NBSA. Both the proposed methods are direct visual titration methods and are more simple than, and superior to, the existing methods for the determination of sulpha drugs.

Department of Chemistry, Holkar Science College, Indore Manuscript received 25 October 1975; accepted 11 February 1976 The complexes of Sulphaguanidine with copper, zinc and cadmium when studied by conducto­metric titration and Job's method of continuous variation showed 1 : 1 complexation. Their stability constants and free energy of formation have been evaluated by employing Job's method of equimolar and non-equimolar solution using optical density and conductance as index property and also poten tiometrically using Calvin Bjerrum \(p\)H titration technique.

6 out of 7 patients with severe neutropenia associated with the use of amodiaquine for malaria prophylaxis amodiaquine (400 mg weekly) plus proguanil (200 mg daily); 1 of these patients had also taken cotrimoxazole and another had taken sulphaguanidine. The 7th patient had taken amodiaquine alone, but at a higher dose. A retrospective analysis suggests that the frequency of severe neutropenia complicating amodiaquine taken prophylactically may be as high as 1 in 2000.

The formation constants of palladium with chloride ions have been determined by a new approach to the interpretation of the ultraviolet spectra. The interaction of PdCl 4 2− with sulphaguanidine (SG) has been interpreted and evaluated quantitatively. The formation constants of the mixed ligand complex Pd(SG) 2 ,Cl 2 , were determined spectrophotometrically. The stability constants for the stepwise formation of the palladium chloride complexes are: log k 1 = 3.48; log k 2 = 2.79; log k 3 = 2.35; log k 4 = 1.1, and for the interaction of PdCl 4 2− with SG, log k 1 = 5.42; log k 2 = 4.38.

A gravimetric method of assay for pyrimethamine, using phosphotungstic acid as precipitant, is described. Assay procedures are given for three preparations of the drug, viz. Tablets of pyrimethamine, Tablets of pyrimethamine and quinine, and Powder of pyrimethamine and sulphaguanidine. Tests of identity for pyrimethamine, additional to those described in the British Pharmaceutical Codex, are also given.