Molecular Aspects of the Interactions between Selected Benzodiazepines and Common Adulterants/Diluents: Forensic Application of Theoretical Chemistry Methods

Abstract

Benzodiazepines are frequently encountered in crime scenes, often mixed with adulterants and diluents, complicating their analysis. This study investigates the interactions between two benzodiazepines, lorazepam (LOR) and alprazolam (ALP), with common adulterants/diluents (paracetamol, caffeine, glucose, and lactose) using infrared (IR) spectroscopy and quantum chemical methods. The crystallographic structures of LOR and ALP were optimized using several functionals (B3LYP, B3LYP-D3BJ, B3PW91, CAM-B3LYP, M05-2X, and M06-2X) combined with the 6-311++G(d,p) basis set. M05-2X was the most accurate when comparing experimental and theoretical bond lengths and angles. Vibrational and ¹³C NMR spectra were calculated to validate the functional's applicability. The differences between LOR's experimental and theoretical IR spectra were attributed to intramolecular interactions between LOR monomers, examined through density functional theory (DFT) optimization and quantum theory of atoms in molecules (QTAIM) analysis. Molecular dynamics simulations modeled benzodiazepine-adulterant/diluent systems, predicting the most stable structures, which were further analyzed using QTAIM. The strongest interactions and their effects on IR spectra were identified. Comparisons between experimental and theoretical spectra confirmed spectral changes due to interactions. This study demonstrates the potential of quantum chemical methods in analyzing complex mixtures, elucidating spectral changes, and assessing the structural stability of benzodiazepines in forensic samples.

Keywords: DFT; IR; QTAIM; adulterants; benzodiazepines; psychoactive substances.

Figure 1

Optimized structures (at the M05-2X/6-311++G(d,p) level of theory) of (a) lorazepam and (b) alprazolam. (Hydrogen = white, carbon = gray, nitrogen = blue, oxygen = red, chlorine = green).

Figure 2

Experimental (black line) and theoretical (at M05-2X/6-31+G(d,p), blue line) IR spectra of (a) monomer and (b) dimer of lorazepam.

Figure 3

Structures with presented interactions within crystal structure (at the B3LYP/6-31G(d,p) level of theory, CrystalExplorer). (Hydrogen = white, carbon = gray, nitrogen = blue, oxygen = red, chlorine = green, green dashed lines represent hydrogen bonds, and red dashed lines represent close contacts).

Figure 4

(a,b) QTAIM molecular graphs of the most stable dimer structures (at the M05-2X/6-31+G(d,p) of LOR. Dashed lines represent the bond paths. (Hydrogen—white, carbon—gray, nitrogen—blue, oxygen—red, chlorine—green).

Figure 5

Possible interactions between lorazepam and adulterants/diluents. (Hydrogen—white, carbon—gray, nitrogen—blue, oxygen—red, chlorine—green, hydrogen bonds—green dashed line).

Figure 6

Possible interactions between alprazolam and adulterants/diluents. (Hydrogen—white, carbon—gray, nitrogen—blue, oxygen—red, chlorine—green, hydrogen bonds—green dashed line).

Figure 7

QTAIM molecular graphs of the most stable structures (at the M05-2X/6-31+G(d,p) level of theory) formed between LOR and (a) paracetamol and (b) caffeine. Dashed lines represent the bond paths. (Hydrogen—white, carbon—gray, nitrogen—blue, oxygen—red, chlorine—green).

Figure 8

Experimental (black line) and theoretical (at the M05-2X/6-31+G(d,p) level of theory, blue line) IR spectra of LOR extract with (a) paracetamol and (b) caffeine.

Figure 9

QTAIM molecular graphs of the most stable structures (at the M05-2X/6-31+G(d,p) level of theory) formed between LOR and (a) glucose and (b) lactose. Dashed lines represent the bond paths. (Hydrogen—white, carbon—gray, nitrogen—blue, oxygen—red, chlorine—green).

Figure 10

Experimental (black line) and theoretical (at the M05-2X/6-31+G(d,p) level of theory, blue line) IR spectra of the LOR tablet with lactose.

Figure 11

QTAIM molecular graphs of the most stable structures (at the M05-2X/6-31+G(d,p) level of theory) formed between ALP and (a) paracetamol and (b) caffeine. Dashed lines represent the bond paths. (Hydrogen—white, carbon—gray, nitrogen—blue, oxygen—red, chlorine—green).

Figure 12

QTAIM molecular graphs of the most stable structures (at the M05-2X/6-31+G(d,p) level of theory) formed between ALP and (a) glucose and (b) lactose. Dashed lines represent the bond paths. (Hydrogen—white, carbon—gray, nitrogen—blue, oxygen—red, chlorine—green).