Density Functional Theory and Density Functional Tight Binding Studies of Thiamine Hydrochloride Hydrates

Abstract

Thiamine hydrochloride (THCL), also known as vitamin B₁, is an active pharmaceutical ingredient (API), present on the list of essential medicines developed by the WHO, which proves its importance for public health. THCL is highly hygroscopic and can occur in the form of hydrates with varying degrees of hydration, depending on the air humidity. Although experimental characterization of the THCL hydrates has been described in the literature, the questions raised in previously published works suggest that additional research and in-depth analysis of THCL dehydration behavior are still needed. Therefore, the main aim of this study was to characterize, by means of quantum chemical calculations, the behavior of thiamine hydrates and explain the previously obtained results, including changes in the NMR spectra, at the molecular level. To achieve this goal, a series of DFT (CASTEP) and DFTB (DFTB+) calculations under periodic boundary conditions have been performed, including molecular dynamics simulations and GIPAW NMR calculations. The obtained results explain the differences in the relative stability of the studied forms and changes in the spectra observed for the samples of various degrees of hydration. This work highlights the application of periodic DFT calculations in the analysis of various solid forms of APIs.

Keywords: CASTEP; DFT; DFTB; GIPAW; hydrate; ssNMR; thiamine hydrochloride.

Figure 1

Chemical structure of thiamine cation.

Figure 2

Unit cell of NSH, refcode THIAMC12. Water molecules have been named UL (upper left), BL (bottom left), UR (upper right), and BR (bottom right).

Figure 3

Unit cell of HH, refcode WUWJAA. Water molecules have been named UL (upper left), BL (bottom left), UR (upper right), and BR (bottom right).

Figure 4

Experimental (exp I, exp II) and calculated unit cell dimensions of MH; for better comparison, the equal range of vertical axis–1.2 Å–has been used for all three unit cell lengths (a, b, and c). For MH2W, the arithmetic mean of the results (MH2W BLUR, MH2W ULBL, and MH2W ULUR) was shown.

Figure 5

Experimental (exp I) and calculated unit cell dimensions of HH; for better comparison, the equal range of vertical axis–1.4 Å–has been used for all three unit cell lengths (a, b, and c). For HH2W, the arithmetic mean of the results (HH2W BLUR, HH2W ULBL, and HH2W ULUR) was shown.

Figure 6

Carbon atom numbering of THCL used in the NMR analysis.

Figure 7

Chosen regions of the ¹³C CP MAS NMR spectra of NSH at various degrees of hydration (0.90, 0.41, and 0.04). Reprinted from [28] with permission from Elsevier.

Figure 8

¹³C CP MAS NMR spectra of 0.9 hydrate of NSH. Reprinted from [28] with permission from Elsevier.

Figure 9

The chosen region of the ¹³C CP MAS NMR spectra of HH and the partially dehydrated form of HH named HH₂. Asterisk indicates spinning sideband. Reprinted from [27] with permission from Elsevier.

Figure 10

Optimized crystal unit cell of HH4W; pink dashed lines represent the intermolecular interactions. Atom coloring: N—blue, C grey, S—yellow, H—white, and O—red. The colors of symmetry equivalent Cl atoms are either violet (Cl1) or green (Cl2).

Figure 11

Optimized crystal unit cells of HH4W, HH3W, HH2W, HH1W, and HH0W. For comparison, please refer to Figure 10.