Acid hydrolysis indomethacin

Replacing the 5-MeO substituent of indomethacin with a Me2N group produced a compound with higher water solubility. This analogue (MK-825, 4.96) was extensively metabolized (ca. 40% in humans) by hydrolysis to 4-chlorobenzoic acid, which was excreted in the urine as 4-chlorobenzoylgly-cine [59]. 

Other API amide hydrolysis examples include chloramphenicol (12), indomethacin under alkaline conditions (13), lidocaine (14), azintamide (15), terazosin (16), flutamide (17), oxazepam, and chlordiazepoxide (18). Lidocaine does not readily hydrolyze in aqueous solution under thermal or basic conditions (Fig. 7) (19). The enhanced stability is due to the steric hindrance of the two o-methyl groups. Hydrolysis does occur more readily in acidic conditions rather than basic conditions presumably because the rate-limiting step, protonation of the carbonyl, is not affected by the steric hindrance of the o-methyl. 

The indomethacin hydrolysis product 2-methyl-5-methoxy indole acetic acid fluoresces at 385 nm after excitation at 300 nm in 0.1N NaOH,(41) and at 387 nm after excitation at 312 nm in pH 11.6 buffer(42). The latter procedure claimed a threefold increase in detectability. Neither method distinguishes indomethacin from salicylates. Clinical studies employing subjects administered aspirin must use a separation prior to fluorescence analysis. Without adequate separation the indole metabolites as well as salicylate, produce a positive assay bias. 

Assessment of indomethacin powder had been specified in the U.J5. XIX and the British Pharmacopeia, 1980 as a back titration with hydrochloric acid after alkaline hydrolysis(13,14). This method can attain a precision of + 0.8%(62). A direct titration for tablets and capsules is described using sodium hydroxide. If performed rapidly with phenolphthalein indicator, a precision of +0.3% is attainable. 8 The latter procedure serves to differentiate ester formation as well as hydrolysis products from intact material. The presence of parachlorobenzoic acid and 5-methoxy-2-methylindole-3-acetic acid are cause for positive error. 

Alkaline hydrolysis of forskolin is inhibited in a lipid emulsion.550 Indomethacin in an oil-water gel is solubilized in the surfactant aggregates and stabilized against acid- and base-catalyzed hydrolysis.551... 

E. Pawelczyk, B. Knitter, and W. Alejska, Drug decomposition kinetics. LVI. Mechanism and kinetics of hydrolysis of indomethacin in the acid medium, Acta Pol. Pharm. 36, 181-188(1979). 

Aqueous solutions of Indomethacin are not stable because of the ease of hydrolysis of the p-chlorobenzoyl group. The original synthesis of Indomethacin by Shen et al. (49) Involved the formation of 2-methyl-5-methoxylndole acetic acid and subsequent ... 

Finally, in Eqn. (d) the resulting product (III) is subjected to hydrolysis in an acidic medium under a blanket of Ng, when the desired product indomethacin is obtained with the elimination of terCbutanol. 

Examples of substances that are prone to hydrolysis are acetylsalicylic acid, ampicillin, barbiturates, chloramphenicol, chlordiazepoxide, cocaine, corticosteroid phosphate or succinate esters, proteins, folinic acid, indomethacin, local anaesthetics, paracetamol (acetaminophen), pilocarpine, tropa alkaloids (atropine, scopolamine), xylomethazoline and the antimicrobial preservatives methyl and propyl parahydroxybenzoate. In the field of oncology, melphalan and bendamustine hydrochloride are highly susceptable to hydrolysis with a shelf life of 1.5 h for melphalan and 3.5 h for bendamustine at room temperature. 

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