Chlordiazepoxide hydrolysis

Hydrolytic cleavage of a seven-membered ring occurs in the metabolism of chlordiazepoxide (5.82, Fig. 5.22,a) and other benzodiazepines (see also Sect. 11.9). The lactam ring opened metabolite 5.83 was detected in humans and dogs and is believed to be generated by hydrolysis of the intermediate lactam [181][182], However, the diazepine ring can be split by other mech-... 

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. 

In the case of xylometazoline hydrochloride, imine hydrolysis chemistry occurs to open the 4,5-dihydro-lH-imidazole ring (Fig. 55) (90). Similar degradation chemistry is observed for the following APIs flurazepam hydrochloride (91), clorazepate dipotassium (92), clonazepam (93), methaqualone (94), chlordiazepoxide, and oxazepam (18). 

The rates of oral absorption of benzodiazepines differ depending on a number of factors, including lipophilicity. Oral absorption of triazolam is extremely rapid, and that of diazepam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines. Clorazepate is converted to its active form, desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach. Oxazepam, lorazepam, and temazepam are absorbed from the gut at slower rates than other benzodiazepines. The bioavailability of several benzodiazepines, including chlordiazepoxide and diazepam, may be unreliable after intramuscular injection. Most of the barbiturates and other older sedative-hypnotics are absorbed rapidly into the blood following their oral administration. 

N-(l-naphthyl)ethylenediamine solution Chlordiazepoxide, oxazepam, and the metabolites of diazepam and medazepam are hydrolysed to 2-amino-5-chlorobenzophenone, which forms a violet dye with the reagents. The test does not distinguish, therefore, between these drugs. The test will detect benzodiazepines in urine at therapeutic concentrations but it is not specific. Any compound that yields an aryl amino group on hydrolysis, e.g. phenylbutazone, will respond to the test. 

The major pathway for chlordiazepoxide metabolism involves hydrolysis of the 2-methylamino substituent to yield the lactam derivative, demoxepam. This is excreted in the urine unchanged or undergoes further cleavage to the corresponding acid before excretion... 

Finally, as examples of lactam ring hydrolysis we can consider the decomposition of nitrazepam and chlordiazepoxide, which is discussed in more detail later (section 4.2.7). Other dmgs, apart from the benzodiazepines, which are susceptible to hydrolysis include the penicillins and cephalosporins. 

Chlordiazepoxide (2) is completely absorbed upon oral administration and reaches peak plasma concentrations in 1-2 h (90). As a highly lipophilic molecule it is 94% bound to plasma proteins (91) and readily penetrates the brain, with CSF levels paralleling unbound plasma levels (92). Chlordiazepoxide has a mean half-life of 15 h. It is metabolized first by oxidative removal of the N-2 methyl group (to give N-desmethylchlordiazepoxide), followed by hydrolysis to the lactam (demox-epam), and reduction of the N-5 oxide to give desmethyldiazepam. All of these metabolites are pharmacologicallyactive. 

The known degradation products of chlordiazepoxide in aqueous solution are shown in Figure 7. In mild acid the lactam is formed while under strong acid treatment, the product of hydrolysis is 2-amino-5-chlorobenzophenone13,... 

The analytical scale liquid-solid chromatographic separation of chlordiazepoxide has been reported by Scott and Bommer in their study of the separation of several benzodiazepines from each other and from biological media27. The important advantages indicated for this method of analysis are the mild operating conditions which enable collection of the compounds and also the simple sample preparation which does not require derivatization or hydrolysis of the sample. 

J.A.F. deSilva has reported the determination of chlordiazepoxide in blood with a sensitivity limit of 0.5 to 0.8 pg/ml of blood2 . The method involves the selective extraction of the compound into ether, hydrolysis to the 2-amino-5-chlorobenzophenone and subsequent determination by gas-liquid chromatography. 

The colorimetric analysis of chlordiazepoxide is accomplished by acid hydrolysis of the compound followed by diazotization and coupling with N-(1-Napthyl)ethylene-diamine dihydrochloride. The resultant reaction product exhibits a maxima at 540 nm. Similar procedures have been reported in the literature which employed other coupling reagents30 31. 

The acid hydrolysis products for both diazepam and its major metabolite are shown in Figure 7. The acid hydrolysis of chlordiazepoxide is also included since it is the same as for the major diazepam metabolite13. 

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. 

Benzodiazepines and their metabolites are normally excreted as the glucuronide conjngates and require either acid or enzyme hydrolysis for good recovery. Hydrolysis of the benzodiazepines yields the corresponding benzophenone, which can be identified by GCMS and related back to the parent benzodiazepine. In some cases, however, the specific benzodiazepine cannot be identified because some benzodiazepines yield the same benzophenone after acid hydrolysis. In addition, some benzodiazepines yield the same metabolites. For example, diazepam and chlordiazepoxide both metabolize to desmethyldiazepam and oxazepam. To eliminate this problem and lower the limit of detection, it is possible to derivatize the benzodiazepines using BSTFA to form their trimethylsilyl derivatives. 

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