Indomethacin

Indomethacin (Shen et al. 1963), one of the first nonsteroidal anti-inflammatory drugs (NSAIDs), is known to exist in three different solid forms. The three forms have different XRPD patterns, and additional chemical analysis indicates that there are no solvates involved with these three forms. Different DTA melting point behaviors (Figs. 3-1 and 3-2) are also observed, as predicted. Forms I and II show single melting point endotherms with peak temperatures of 163°C and 157°C, respectively. Form III shows an initial melting endotherm with a peak temperature of 151 °C followed by an exotherm that corresponds to the crystallization of Form I, which then melts, yielding the endotherm with a peak temperature of 163°C. 

Solubility data at 25°C (Table 3-1) indicate that Form I is also the most stable form at the lower temperatures. The solubility measurements were performed in water at constant temperature and pH because indomethacin is a carboxylic acid and changes in pH would affect its solubility, as would changes in temperature. 

From these results, it was concluded that the pairs of polymorphs are monotropic and that Form I is the most stable modification of the three indomethacin polymorphs. 

Isolation of the individual polymorphs of indomethacin was initially accomplished by trial and error. There was no absolute way of predicting that there would be polymorphism with indomethacin or any other compound, for that matter. Initially, crystallization under different conditions for process reasons, not for the search for polymorphs, produced different solid phases that were shown to be polymorphs of indomethacin, as indicated above. 

Generally, Form I results from controlled crystallizations, either by slow cooling with adequate mixing or slow addition of an antisolvent with adequate mixing at a constant temperature. Form II usually results from rapid crystallizations with either temperature or antisolvent. Even after initial isolation of Form III of indomethacin, it was difficult to predict when it would be obtained, but the conditions were usually somewhat chaotic. Serendipity appears to be a major factor in the isolation of Form III. 

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One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

Synthetic Derivatives of Indoles as Pharmaceuticals. Thousands of indole derivatives have been prepared and evaluated as potential pharmaceuticals (32). Of those which have been put into use perhaps the most important are the nonsteroidal antiinflammatory agent indomethacin [53-86-1] (10) (33) and the p-adrenergic blocker pindolol [13823-86-9] (11) (34). 

Nonsteroidal Antiinflammatory Drugs. Nonsteroidal antiinflammatory dmgs (NSAIDs) include, among the numerous agents of this class, aspirin (acetylsaflcyhc acid), the arylacetic acids indomethacin and sulindac, and the arylpropionic acids, (5)-(147) and (R)-(148) ibuprofen, (5)-(149) and (R)- (150), flurbiprofen naproxen (41), and fenoprofen (see Analgesics, antipyretics, and antiinflammatory agents Salicylic acid and related compounds). 

Paradoxically, the thia2ides are efficacious, especially if combined with a prostaglandin synthetase inhibitor such as indomethacin or aspirin, in the treatment of nephrogenic diabetes insidipus, in which the patient s renal tubules fail to reabsorb water despite the excessive production of ADH (28). Thia2ides can decrease the urine volume up to 50% in these patients. 

Indolo[2,3-d][l,3]thiazine-2,4-dithione formation, 4, 299 Indolothiazines synthesis, 4, 519 Indoloyl azides Curtius rearrangement, 4, 288 Indolyl anions acylation, 4, 232 alkylation, 4, 235 Michael-type additions, 4, 236 Indomethacin... 

Flurbiprofen and indomethacin, which comprise the third class of inhibitors, cause a slow, time-dependent inhibition of COX-1 and COX-2, apparently via formation of a salt bridge between a carboxylate on the drug and Arg , which lies in the tunnel. 

Though the therapeutic utility of aspiri n has been recognized for well over a century, this venerable drug was not classified as a nonsteroid antiinflammatory until recently. The first drug to be so classified was in fact, indomethacin (1), a very useful agent introduced... 

Replacement of chlorine on the pendant benzoyl group by azide is apparently consistent with antiinflammatory activity. Acylation of indomethacin intermediate with p-nitrobenzoyl chloride leads to the corresponding amide (7). Saponification ( ) followed by reduction of the nitro group gives the amine 9. The diazonium salt (10) obtained on treatment with nitrous acid is then reacted with sodium azide there is thus obtained zidomethacin (11). 

Chlorobenzyl chloride Ambenonium chloride Ticlopidine HCI p-Chlorobenzyl chloride Clobutinol Echonazole nitrate Indomethacin Pyrrobutamine Triparanol... 

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