Simultaneous estimation of dimenhydrinate, cinnarizine and their toxic impurities benzophenone and diphenylmethylpiperazine; in silico toxicity profiling of impurities.

Nada S Abdelwahab,Fadwa H Edrees,Mohammed T Alsaadi,Noha H Amin,Ahmed S Saad

doi:10.1039/d0ra06147f

Nada S Abdelwahab, Fadwa H Edrees + Show 3 more

Open Access

https://doi.org/10.1039/d0ra06147f

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Abstract

The British Pharmacopeia (BP) reported that the carcinogenic and hepatotoxic, benzophenone (BZP) is a dimenhydrinate (DMH) impurity. On the other hand, cinnarizine (CIN) is reported to have five impurities (A–E). The toxicity profile of CIN impurities was studied and the in silico data revealed that impurity A [1-(diphenylmethyl)piperazine] (DPP) was the most toxic CIN impurity, and hence it was selected during this work. TLC-densitometric method was developed for separation and simultaneous quantitation of DMH, CIN and their toxic impurities. In the proposed method hexane : ethanol : acetone : glacial acetic acid (7 : 3 : 0.7 : 0.5, by volume) with UV scanning at 225 nm were used. Method validation was carried out according to ICH guidelines and linearity was achieved in the range 0.2–4, 0.5–5, 0.1–2.0, and 0.05–2.2 μg per band for DMH, CIN, BZP and DPP, respectively. On the application of the method to pharmaceutical formulation, no interference from additives was observed. The greenness of the method was evaluated using the analytical eco-scale and the results revealed the low negative environmental impact of the developed method.

Highlights

Dimenhydrinate (DMH), is the theoclate salt of diphenhydramine (DIP) that is chemically named, 1-((2-(benzhydryloxy)ethyl)(methyl)amino)-8-chloro-3-methyl-3,7-dihydro-1H-purine-2,6dione, (Fig. 1a).[1]
The in silico toxicity pro ling was studied for CIN impurities and results showed that DPP had the highest toxicity among all CIN impurities (A–E)
A novel, accurate and precise TLC-densitometric method has been developed for the simultaneous determination of DMH, CIN and their toxic impurities; BZP and DPP, respectively

Summary

Introduction

Dimenhydrinate (DMH), is the theoclate salt of diphenhydramine (DIP) that is chemically named, 1-((2-(benzhydryloxy)ethyl)(methyl)amino)-8-chloro-3-methyl-3,7-dihydro-1H-purine-2,6dione, (Fig. 1a).[1] DMH has antihistaminic and antimuscarinic activities with signi cant sedative and addictive effects.[1,2,3] the antiemetic DMH is traditionally used in the treatment of motion sickness and peripheral vestibular vertigo.[4]. DMH has several official impurities,[5] only toxicity assessment was available for benzophenone (BZP), (Fig. 1b) and Cinnarizine (CIN), 1-(diphenylmethyl)-4-(3-phenyl-2propenyl)piperazine (Fig. 1d) is a piperazine derivative with antihistaminic and calcium channel blocking activities. It improves the cerebral blood ow it is used in the treatment of cerebral arteriosclerosis, cerebral apoplexy, and post-traumatic cerebral signs. CIN is used for the management of nausea, vomiting, vertigo, motion sickness, and Meniere's disease.[14,15,16]

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