Sulfanilamide preparation

An un-safely formulated sulfanilamide preparation kills 107 people, mainly children. 

The NDA process and the role of pharmacoepidemiology in the United States have evolved since the Food, Drug, and Cosmetic (FD C) Act of 1938 was enacted into law. The FD C Act was adopted following the deaths of more than 100 patients of renal failure from sulfanilamide prepared in a diethylene glycol vehicle. For the first time in U.S. history, the act required a drug to be proven safe under... 

The purity of a pharmaceutical preparation of sulfanilamide, C6H4N2O2S, can be determined by oxidizing the sulfur to SO2 and bubbling the SO2 through H2O2 to produce H2SO4. The acid is then titrated with a standard solution of NaOH to the bromothymol blue end point, where both of sulfuric acid s acidic protons have been neutralized. Calculate the purity of the preparation, given that a 0.5136-g sample required 48.13 mL of 0.1251 M NaOH. 

Let s use a simple example to develop the rationale behind a one-way ANOVA calculation. The data in Table 14.7 show the results obtained by several analysts in determining the purity of a single pharmaceutical preparation of sulfanilamide. Each column in this table lists the results obtained by an individual analyst. For convenience, entries in the table are represented by the symbol where i identifies the analyst and j indicates the replicate number thus 3 5 is the fifth replicate for the third analyst (and is equal to 94.24%). The variability in the results shown in Table 14.7 arises from two sources indeterminate errors associated with the analytical procedure that are experienced equally by all analysts, and systematic or determinate errors introduced by the analysts. 

Results of Four Analysts for the % Purity of a Preparation of Sulfanilamide... 

Table 14.7 shows the results obtained by four analysts determining the purity of a pharmaceutical preparation of sulfanilamide. Determine if the difference in their results is significant at a = 0.05. If such a difference exists, estimate values... 

A monograph (1) covers the pioneering period of sulfa dmg development and describes over 5000 sulfanilamide derivatives, their preparation, properties, trade names, and biological testing. This review is remarkably complete through 1944. Several thousand additional derivatives have been made since, but no comparable coverage is available. A definitive account of medical appHcations up to 1960 has been pubHshed (2), and a review of experimental antibacterial aspects has been made (3). Chapters on general aspects of sulfonamides and sulfones have appeared (4,5). A review of the clinical efficacy of trimethoprim—sulfamethoxazole has been pubHshed (6). 

In a few cases, A/ -heterocycHc sulfanilamides have been prepared by the condensation of an active heterocycHc haHde with the sulfonamide nitrogen of sulfanilamide or its A/-acetyl derivative in the presence of an acid-binding agent. Sulfapyridine, sulfadiazine, and sulfapyrazine have been made by this method (1), but the most important appHcation is probably for the synthesis of sulfachlorapyridazine (9) and sulfamethoxypyridazine (10) (45). 

The most commonly used methods for the preparation of pyridazinesulfonamides are the condensation of aminopyridazines with p-acylaminobenzenesulfonyl chloride and the reaction of halosubstituted pyridazines with sulfanilamide by fusion or in an appropriate solvent. 

A sulfanilamide drug of prolonged action, 2-p-aminobenzenesulfamido-4-methylpyiimidine (sulfomerazine 162), first prepared by Japanese chemists from acetacetic aldehyde in 82% yield (49JPJ447), ranks among practically valuable 2-amino-4-methylpyrimidine derivatives. Later, a synthesis of this product directly from l-methoxybut-l-en-3-yne (100°C, AcONa, AcOH, 3 h) in 64% yield has been developed (76MI1). 

Generally, N -acylsulfonamides are less effective than those having a single N -aryl group. One such acyl analogue, sulfabenzamide (130) is prepared simply from sulfanilamide (128) by bisbenzamide formation (to 129) using benzoyl chloride and pyridine,... 

Dibromoaniline has been prepared many times 3"5 6 n by bromination of sulfanilic acid and desulfonation of the product or its salts. Fuchs12 brominated sulfanilamide with free bromine and desulfonamidated it in the usual manner. Reduction of the corresponding nitro compound13 and other methods 14 also have been employed. 

The first reports from Tulsa led the FDA to dispatch the agency s chief medical officer, Theodore G. Klumpp, accompanied by an inspector, William T. Ford, from Cincinnati, to the plant in Bristol at which Elixir Sulfanilamide had been conceived and first prepared (21, 22) ... 

Raman often is evaluated as an alternative to an existing high performance liquid chromatography (HPLC) method because of its potential to be noninvasive, fast, simple to perform, and solvent-free. Raman was compared to HPLC for the determination of ticlopidine-hydrochloride (TCL) [43], risperidone [44] in film-coated tablets, and medroxyprogesterone acetate (MPA) in 150-mg/mL suspensions (DepoProvera, Pfizer) [45] it was found to have numerous advantages and performance suitable to replace HPLC. In an off-line laboratory study, the relative standard deviation of the measurement of the composition of powder mixtures of two sulfonamides, sulfathiazole and sulfanilamide, was reduced from 10-20% to less than 4% by employing a reusable, easily prepared rotating sample cell [46]. 

Similar success was achieved in the synthesis of analogs of prontosil and sulfanilamide. A number of these analogs were prepared and tested and found to he effective against a variety of infectious diseases. 

Lipmann wondered what nature used in their place. His approach in seeking the biological "active acetate" is one that has been used successfully in solving many biochemical problems. He first set up a test system to examine the ability of extracts prepared from fresh liver tissue to catalyze the acetylation of sulfanilamide (Eq. 14-2). A specific color test was available for quantitative determination of very small amounts of the... 

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