This review discusses a set of instrumental and computational methods that are used to characterize hydrated forms of APIs (active pharmaceutical ingredients). The focus has been put on highlighting advantages as well as on presenting some limitations of the selected analytical approaches. This has been performed in order to facilitate the choice of an appropriate method depending on the type of the structural feature that is to be analyzed, that is, degree of hydration, crystal structure and dynamics, and (de)hydration kinetics. The presented techniques include X-ray diffraction (single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD)), spectroscopic (solid state nuclear magnetic resonance spectroscopy (ssNMR), Fourier-transformed infrared spectroscopy (FT-IR), Raman spectroscopy), thermal (differential scanning calorimetry (DSC), thermogravimetric analysis (TGA)), gravimetric (dynamic vapour sorption (DVS)), and computational (molecular mechanics (MM), Quantum Mechanics (QM), molecular dynamics (MD)) methods. Further, the successful applications of the presented methods in the studies of hydrated APIs as well as studies on the excipients’ influence on these processes have been described in many examples.

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Cyclodextrins (CDs) are highly respected for their ability to form inclusion complexes via host–guest noncovalent interactions and, thus, ensofance other molecular properties. Various molecular modeling methods have found their applications in the analysis of those complexes. However, as showed in this review, molecular dynamics (MD) simulations could provide the information unobtainable by any other means. It is therefore not surprising that published works on MD simulations used in this field have rapidly increased since the early 2010s. This review provides an overview of the successful applications of MD simulations in the studies on CD complexes. Information that is crucial for MD simulations, such as application of force fields, the length of the simulation, or solvent treatment method, are thoroughly discussed. Therefore, this work can serve as a guide to properly set up such calculations and analyze their results.

This review focuses on a combination of ab initio molecular dynamics (aiMD) and NMR parameters calculations using quantum mechanical methods. The advantages of such an approach in comparison to the commonly applied computations for the structures optimized at 0 K are presented. This article was designed as a convenient overview of the applied parameters such as the aiMD type, DFT functional, time step, or total simulation time, as well as examples of previously studied systems. From the analysis of the published works describing the applications of such combinations, it was concluded that including fast, small-amplitude motions through aiMD has a noticeable effect on the accuracy of NMR parameters calculations.

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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.

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The aim of this study was to determine whether the periodic density functional theory (DFT) calculations can be used for accurate prediction of the influence of the increased pressure on crystal structure and stability of molecular solids. To achieve this goal a series of geometry optimization and thermodynamic parameters calculations were performed for γ-glycine and δ-glycine structures at different pressure values using CASTEP program. In order to perform most accurate geometry optimization various exchange-correlation functionals defined within generalized gradient approximation (GGA): PBE, PW91, RPBE, WC, PBESOL as well as defined within local density approximation (LDA), i.e. CAPZ, were tested. Geometry optimization was carried out using different dispersion correction methods (i.e. Grimme, TS, OBS) or without them. The linear response density functional perturbation theory (DFPT) was used to obtain the phonon dispersion curves and phonon density of states from which thermodynamic parameters, such as: free energy (ΔG), enthalpy (ΔH) and entropy (ΔS) were evaluated. The results of the geometry optimization depend strongly on the choice of the DFT functional. Calculated differences between the free energy of the studied polymorphic forms at the studied pressure values were consistent with experimental observations on their stability. The computations of thermodynamic properties not only confirmed the order of stability of two studied forms, but also enabled to predict the pressure at which this order is reversed. The results obtained in this study have proven that the plane-wave basis set first principles calculations under periodic conditions is suitable for accurate prediction of crystal structure and stability. © 2018 Wiley Periodicals, Inc.