Periodic DFT Calculations-Review of Applications in the Pharmaceutical Sciences

Abstract

In the introduction to this review the complex chemistry of solid-state pharmaceutical compounds is summarized. It is also explained why the density functional theory (DFT) periodic calculations became recently so popular in studying the solid APIs (active pharmaceutical ingredients). Further, the most popular programs enabling DFT periodic calculations are presented and compared. Subsequently, on the large number of examples, the applications of such calculations in pharmaceutical sciences are discussed. The mentioned topics include, among others, validation of the experimentally obtained crystal structures and crystal structure prediction, insight into crystallization and solvation processes, development of new polymorph synthesis ways, and formulation techniques as well as application of the periodic DFT calculations in the drug analysis.

Keywords: API; CASTEP; DFT; crystal; periodic.

Figure 1

Results of Gauge Including Projector Augmented Waves Nuclear Magnetic Resonance (GIPAW NMR) chemical shielding anisotropy calculations for the N atom of the α glycine crystal structures. On the left powder X-ray diffraction (PXRD) structure (−12.87 ppm), on the right single crystal X-ray diffraction (SCXRD) structure (−23.81 ppm). Experimental value: −12.35 ppm. Source: author’s archive, more details [71].

Figure 2

Possible options in the area of periodic density functional theory (DFT) calculations for crystals. Once the crystal structure is obtained and validated, it can be used to calculate other properties, such as thermodynamics or spectroscopic data. XFS stands for X-ray fluorescence.

Figure 3

Results of thermodynamics calculations for three polymorphs of nootropic drug, piracetam. The energy of the lowest energy form at given T is, at that T, the reference one and its value is set to zero. Using periodic DFT calculations it was possible to determine the order of stability of those three studied forms. The calculated results were in agreement with the experimental data, that is the Polymorph 3 is the most stable one at low temperatures until it transforms into Polymorph 1 which is the most stable one at high temperatures. The Polymorph 2 is metastable in the whole temperature range. Source: author’s archive, more details [116].

Figure 4

Results of thermodynamics calculations at constant temperature (298 K) and variable pressure for crystalline glycine, the differences between the free energy of δ and α polymorphs. Calculated values support the experimentally observed high pressure induced phase transition of α to δ polymorph. Source: author’s archive, more details [139].

Figure 5

Results of molecular dynamics calculations at 3.10 GPa for urea Form I, unit cell lengths profiles. A phase transition is observed after 6 ps of simulation. The results were found to be in agreement with the experimental data as Form I is metastable and transforms into Form IV at 3.10 GPa. Source: author’s archive, more details [160].

Figure 6

Results of Nuclear Magnetic Resonance (NMR) calculations for trans-cinnamic acid. On top using periodic DFT (GIPAW CASTEP), below using single molecule (GIAO Gaussian). By using periodic DFT calculations not only higher coefficient of determination (R²) but also slope closer to 1 were achieved. Source: author’s archive, more details [187].

Figure 7

Results of GIPAW NMR calculations for tiotropium bromide monohydrate. On top is the experimental structure with solely hydrogen atoms positions optimized (188.54 ppm for C6 and 107.01 ppm for C12), below is the structure after all atom’s positions optimization (151.24 ppm for C6 and 127.64 ppm for C12). Experimental values: 148.91 ppm for C6 and 127.77 ppm for C12. Source: author’s archive, more details [207].