Elucidation of Degradation Behavior of Tricyclic Antidepressant Amoxapine in Artificial Gastric Juice

Abstract

The degradation behavior of eight tricyclic antidepressants (TCAs; amitriptyline, amoxapine (AMX), imipramine, clomipramine, desipramine, doxepin, dothiepin, and nortriptyline) in artificial gastric juice was investigated to estimate their pharmacokinetics in the stomach. As a result, among the eight TCAs, only AMX was degraded in artificial gastric juice. The degradation was a pseudo first-order reaction; activation energy (Ea) was 88.70 kJ/mol and activation entropy (ΔS) was 80.73 J/K•mol. On the other hand, the recovery experiment revealed that the degradation product did not revert to AMX and accordingly, this reaction was considered to be irreversible. In the AMX degradation experiment, peaks considered to be degradation products A (I) and B (II) were detected at retention times of around 3 min and 30 min in LC/UV measurements, respectively. Structural analysis revealed that compound (I) was [2-(2-aminophenoxy)-5-chlorophenyl]-piperazin-1-yl-methanone, a new compound, and compound (II) was 2-chlorodibenzo[b,f][1,4]oxazepin-11(10H)one. As for the degradation behavior, it was estimated that AMX was degraded into (II) via (I), i.e., (II) was the final product. The results are expected to be useful in clinical chemistry and forensic science, including the estimation of drugs to be used at the time of judicial dissection and suspected drug addiction.

Elucidation of Degradation Behavior of Nitrazepam and Other Benzodiazepines in Artificial Gastric Juice: Study on Degradability of Drugs in Stomach (II)

“…NZP Long-Term Degradability Verification Experiment NZP is known to form benzophenone compounds as the final degradation products through intermediates under acidic conditions. [10][11][12][13] From a detailed re-examination of the degradability of NZP in artificial gastric juice, we confirmed that two degradation products were produced from NZP in addition to NZP itself (Fig. 3).…”

“…For this reason, past studies of BZP degradation behavior inferred the time course of the degradation by monitoring the acid hydrolysis of BZPs by spectrophotometry 10,11) and polarography. 12) In our previous work, 13) we elucidated the degradation behavior of tricyclic antidepressant amoxapine in artificial gastric juice. In this study, we reconfirmed the degradation behavior of eight frequently used BZPs (alprazolam, etizolam, diazepam, triazolam, nitrazepam (NZP), FNZ, bromazepam, and lorazepam) in artificial gastric juice to infer their pharmacokinetics in stomach.…”

“…As for NZP, it was reported that 2-amino-5-nitrobenzophenone was actually isolated and purified as the degradation product under acidic conditions. 12,14) On the other hand, although the existence and the structural formula of an intermediate were estimated, 10) its detailed structural information could not be determined because the intermediate was difficult to isolate and purify. Only Davidson and Smail 15) were able to isolate the acid hydrolysate of NZP (intermediate and final degradation product) by liquid-liquid extraction and to estimate the intermediate by instrumental analyses.…”

An Overview of Degradation Strategies for Amitriptyline

“…The recovery of NTRI (nortriptyline) by treatment plants in Canada was as high as 92 ± 1% [70]. The degradation of NTRI was fast in aqueous fulvic acid solution (k = 0.16 h −1 ) [53], but the acidity of artificial gastric juice did not cause any degradation of NTRI [94], which pointed out a different operating mechanism. A toxic effect on the aquatic system has been observed in the case of zebrafish (Danio rerio) by inhibiting the acetylcholinesterase activity, which provoked an anxietylike state due to the impairment of the enzymes [20].…”

“…Additionally, specific drug-drug interactions may accelerate degradation, especially when antidepressants are co-administered with other medications. Proper knowledge of degradation pathways for antidepressants can guide the development of suitable storage conditions and packaging materials shielding the drugs from environmental factors inducing degradation [72,94].…”