Elucidation of Degradation Behavior of Hydroxy Group-Containing Benzodiazepines in Artificial Gastric Juice: Study on Degradability of Drugs in Stomach (III)

Abstract

The degradation behavior of three benzodiazepines (BZPs)-lormetazepam (LMZ), lorazepam, and oxazepam-with hydroxy groups on the diazepine ring in artificial gastric juice and the effect of storage pH conditions on drug degradability were monitored using an LC/photodiode array detector (PDA) to estimate their pharmacokinetics in the stomach. Although the three BZPs degraded in artificial gastric juice, none could be restored, despite increasing the storage pH, implying that the degradation reaction was irreversible. As for LMZ, we discussed the physicochemical parameters, such as the activation energy and activation entropy involved in the degradation reaction as well as the reaction kinetics; one of the degradation products was isolated and purified for structural analysis. In the LMZ degradation experiment, peaks corresponding to degradation products, (A) and (B), were detected through the LC/PDA measurements. Regarding the degradation behavior, we hypothesized that LMZ was degraded into (B) via (A), where (A) was an intermediate and (B) was the final product. Although the isolation of degradation product (A) was challenging, degradation product (B) could be isolated and was confirmed to be "methanone, [5-chloro-2-(methylamino) phenyl]-(2-chlorophenyl)-" based on structure determination using various instrumental analyses. The compound exhibited axis asymmetry as determined using single-crystal X-ray structure analysis. Because the formation of degradation product (B) was irreversible, it would be prudent to target the final degradation product (B) and LMZ for identification when detecting LMZ in human stomach contents, such as during forensic dissection.

Elucidation of Degradation Behavior of Nitrazepam, a Benzodiazepine Drug, under Basic Conditions: Study on Degradability of Drugs in Stomach (IV)

“…Our group has investigated the degradation behavior of psychotropic drugs such as BZPs and tricyclic antidepressants in artificial gastric juice. [9][10][11] The results revealed the degradation pathway of amoxapine, 9) nitrazepam, 10) and lormetazepam, 11) and we have also determined some degradation products of such drugs. In addition, the long-term degradation behavior of NZP under acidic condition was observed and the results revealed the presence of a degradation intermediate (2-amino-N-(2-benzoyl-4-nirophenyl)-acetamide) and a final degradation product (2-amino-5-nitrobenzophenone).…”

“…The degradation experiment of NZP was carried out according to the flunitrazepam degradation test. 10) To 900 µL of 1 mol/L NaOH aqueous solution, 100 µL of NZP standard solution (1000 µg/mL) was added. The solutions were then stored in an incubator set to 80 °C.…”

“…The aliquot of the methanol-d 4 solution of the degradation product used in the NMR measurements was further diluted with methanol to a definite concentration for the recording of UV spectra using The chemical reaction pathway from (I) to (IV) passing by (III) is the previously reported definite degradation pathway under acidic condition. 10) LC/PDA and accurate molecular weight determination using LC/TOF-MS. The remaining methanol-d 4 solution of the degradation product was again evaporated and the residue was dissolved in an HCl/diethyl ether solution (3 mL, 1 mol/L) to crystallize.…”

“…In addition, the long-term degradation behavior of NZP under acidic condition was observed and the results revealed the presence of a degradation intermediate (2-amino-N-(2-benzoyl-4-nirophenyl)-acetamide) and a final degradation product (2-amino-5-nitrobenzophenone). 10) However, if the body is left for a long period and decomposition progresses, as in the case reported by Bolte et al, 8) basic polyamines and ammonia, known as putrefactive amines such as putrescine, cadaverine, spermidine, and spermine, are expected to be generated inside the body. Consequently, to detect BZPs in a decomposed corpse, it is essential to understand the degradation behavior of BZPs under both acidic (caused by gastric juice) and basic (caused by putrefaction) conditions.…”

“…Following our previous investigation on the degradation behavior of NZP under acidic conditions, 10) this study investigates the behavior under basic conditions by determining the degradation pathway using an LC/photodiode array detector (PDA), and products where the results revealed that the obtained degradation products produced were different from those reported by Davidson et al 14)…”