Computational and spectral studies of 3,3'-(propane-1,3-diyl)bis(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one)

Abstract

Detection and qualification of unknown impurities during commercial drug synthesis have been mandated by the regulatory authorities. 3,3'-(propane-1,3-diyl)bis(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-benzo [d]azepin-2-one) in short IVA-9, is one such process-related impurity formed during the synthesis of cardiotonic drug Ivabradine. The structure and properties of this molecule have not been explored yet. A suggestive reaction route for the chance formation of IVA-9 during the commercial synthesis of parent drug molecule has been reported in this article. Further, the optimized geometry and vibrational studies have been computed using Gaussian 09. Experimental FTIR scan has also been performed and values show satisfactory consilience with the computational data. The frontier orbital energies and energy band gaps of the reaction fragments and products were computed. The evaluation of ADME parameters such as absorption, distribution, metabolism, and excretion are performed using SwissADME tool to assess the drug-likeness and medicinal chemistry friendliness. Six physiochemical parameters namely flexibility, lipophilicity, size, polarity, solubility and saturation and their critical limits are depicted using the bioavailability radar of the programme to provide insights into pharmacokinetic properties such as human gastrointestinal absorption (HIA), blood-brain-barrier (BBB) permeability, total polar surface area (TPSA) and inhibitor action to important cytochromes etc.

Keywords: ADME studies; Analytical chemistry; Computational; DFT; FTIR; Ivabradine impurity; Pharmaceutical chemistry.

Fig. 1

(a): Ivabradine. (b): IVA-9.

Fig. 2

Literature method for the synthesis of Ivabradine .

Fig. 3

Suggestive reaction route for the formation of IVA-9.

Fig. 4

Horse-shoe shaped form of Ivabradine (Image Credit: National Center for Biotechnology Information. PubChem Database [20]).

Fig. 5

Optimized geometry visualized at DFT/B3LYP/6-311g (H atoms being omitted for the sake of clarity).

Fig. 6

Bond lengths compared (IVA-9).

Fig. 7

Bond angles compared (IVA-9).

Fig. 8

(a): Experimental FTIR spectrum of IVA-9. (b): Computed IR Spectra of IVA-9 @ DFT-B3LYP/6-311g.

Fig. 9

HOMO-LUMO energy gap.

Fig. 10

UV-Visible spectrum of IVA-9.

Fig. 11

(a) Bio-availability radar-Ivabradine. (b): Bio-availability radar-IVA-9.