Matthew D. King

Identification and quantification of polymorphism in the pharmaceutical compound diclofenac acid by terahertz spectroscopy and solid-state density functional theory

Polymorph detection and quantification in crystalline materials is a principle interest of the pharmaceutical industry. Terahertz (THz) spectroscopy can be used for such analytical applications since this technique is sensitive to the intermolecular interactions of molecules in the solid state. Understanding the fundamental nature of the lattice vibrational motions leading to absorptions in THz spectra is challenging, but may be achieved through computational approaches. In this study, the THz spectra of two diclofenac acid polymorphs were obtained by THz spectroscopy, and the vibrational characters of the observed absorptions were analyzed using solid-state density functional theory (DFT). The results demonstrate the quantitative capacity of THz spectroscopy and the reliability and utility of solid-state DFT in the calculation of low-frequency vibrational motions.

Application of London-type dispersion corrections to the solid-state density functional theory simulation of the terahertz spectra of crystalline pharmaceuticals

The effects of applying an empirical dispersion correction to solid-state density functional theory methods were evaluated in the simulation of the crystal structure and low-frequency (10 to 90 cm(-1)) terahertz spectrum of the non-steroidal anti-inflammatory drug, naproxen. The naproxen molecular crystal is bound largely by weak London force interactions, as well as by more prominent interactions such as hydrogen bonding, and thus serves as a good model for the assessment of the pair-wise dispersion correction term in systems influenced by intermolecular interactions of various strengths. Modifications to the dispersion parameters were tested in both fully optimized unit cell dimensions and those determined by X-ray crystallography, with subsequent simulations of the THz spectrum being performed. Use of the unmodified PBE density functional leads to an unrealistic expansion of the unit cell volume and the poor representation of the THz spectrum. Inclusion of a modified dispersion correction enabled a high-quality simulation of the THz spectrum and crystal structure of naproxen to be achieved without the need for artificially constraining the unit cell dimensions.

Discrimination of chiral solids: a terahertz spectroscopic investigation of L- and DL-serine.

The terahertz (THz, far-infrared) spectra of enantiomerically pure and racemic crystalline serine were investigated using time-domain THz spectroscopy and solid-state density functional theory (DFT) in the spectral range of 10-90 cm(-1). The experimental THz spectra of L- and DL-serine at 78 K appear quite similar despite the significant differences in arrangement of the molecules in their crystal structures. Structural analyses of the two systems and calculation of the vibrational modes and intensities were performed using DFT with periodic boundary conditions employing the B3LYP and PW91 density functionals with the 6-31G(d,p) and 6-311G(d,p) basis sets. The applied computational methods produced simulations of the THz spectra in good agreement with experiment, with accurate predictions of the subtle differences in the THz spectra of the two chiral solid-state mixtures of serine. The observed spectral features are assigned as primarily external lattice translations and rotations with lesser contributions due to intramolecular torsions of the -NH(3)(+) and -COO(-) groups modified by intermolecular hydrogen bonding.

Effect of waters of crystallization on terahertz spectra: anhydrous oxalic acid and its dihydrate.

Oxalic acid and oxalic acid dihydrate were studied using terahertz spectroscopy and solid-state density functional theory (DFT) in the spectral range 10-100 cm(-1). The size of the oxalic acid molecule and its limited internal degrees of freedom make it ideal for evaluating the performance of computational methods for the structural and dynamical simulation of strongly hydrogen-bonded solids. Calculations of the solid-state structures and terahertz spectra of oxalic acid and oxalic acid dihydrate were performed using the hybrid B3LYP and B3PW91 and the nonhybrid BLYP and PW91 density functionals employing the 6-311G(2d,2p) basis set. When these simulations were compared to the experimental spectra of the oxalic acid solids, a constant overprediction of the dihydrate frequencies was observed in contrast to the results of the anhydrous system. This change in behavior is connected to the nature of the vibrational motions being accessed. The primary molecular motion contributions to the terahertz vibrations of oxalic acid dihydrate were found to originate in the external motions of the cocrystallized H(2)O molecules. The observed overestimation of the vibrational energies in the simulated terahertz spectra is attributed to increased anharmonicity of the vibrational motions in the dihydrate system versus the anhydrous, resulting from weaker hydrogen bonding through the networked water molecules.

Understanding the Terahertz Spectra of Crystalline Pharmaceuticals: Terahertz Spectroscopy and Solid-State Density Functional Theory Study of (S)-(+)-Ibuprofen and (RS)-Ibuprofen

The potential applications of terahertz (THz) spectroscopy in the analysis of pharmaceutical products in their crystalline state have prompted the need for a more thorough understanding of the fundamental vibrational motions contributing to the THz spectra. The detection of variations in crystal structure and the reliable assignment of observed THz absorption features can be aided by the use of solid-state density functional theory (DFT). In this study, solid-state DFT with periodic boundary conditions was used to simulate the crystalline structure and assign the experimental THz spectra (10-90 cm(-1)) of the enantiomerically pure and racemic forms of the common pharmaceutical compound ibuprofen. The results clearly demonstrate the capabilities of DFT methodologies to accurately reproduce the THz spectra of large complicated molecular systems and provide insight into the internal and external vibrational motions that form the basis of THz spectroscopy.

Noncovalent interactions in paired DNA nucleobases investigated by terahertz spectroscopy and solid-state density functional theory.

Cocrystallized adenine and thymine derivatives, along with the pure monomeric crystals, were investigated by terahertz spectroscopy and solid-state density functional theory (DFT). The methylated nucleobase derivatives crystallize in planar hydrogen-bonded adenine-thymine pairs similar to the manner found in DNA. The spectra obtained for 1-methylthymine, 9-methyladenine, and the 1:1 cocrystal in the range of 10-100 cm(-1) clearly demonstrate that absorptions in this spectral range originate from the uniquely ordered assembly and the intermolecular interactions found in each individual crystal system. The quality of spectral reproduction for the DFT simulations of each system was clearly improved by the inclusion of an empirical correction term for London-type dispersion forces to the calculations. Notably, it was found that these weak dispersion forces in the adenine-thymine cocrystal were necessary to produce a properly converged crystal structure and meaningful simulation of the terahertz vibrational spectrum.

Investigating the anharmonicity of lattice vibrations in water-containing molecular crystals through the terahertz spectroscopy of l-serine monohydrate

The influence of cocrystallized H(2)O molecules on the terahertz (THz) spectra and corresponding computational treatment of hydrated molecular crystals was investigated in the study of protonated and deuterium-substituted l-serine.H(2)O. The THz spectra of both solids have been measured in the range of 10 to 90 cm(-1), with simulations of the crystalline structure and THz vibrational modes performed using solid-state density functional theory. Significant and systematic overestimations of the predicted vibrational frequencies were observed in all calculations. Evidence provided by the comparison of the experimental and calculated vibrational frequencies for both the protonated and deuterated l-serine.H(2)O solids indicates the presence of significant anharmonicity in the observed lattice vibrations. The results suggest that vibrational anharmonicity may play a much larger role in the interpretation of the THz spectra of hydrates in contrast to their corresponding anhydrous forms.

Formation of large-area GaN nanostructures with controlled geometry and morphology using top-down fabrication scheme

This paper details the fabrication of GaN nanoscale structures using deep ultraviolet lithography and inductively coupled plasma (ICP) etching techniques. The authors controlled the geometry (dimensions and shape) and surface morphology of such nanoscale structures through selection of etching parameters. The authors compared seven different chlorine-based etch chemistries: Cl2, Ar, Cl2/N2, Cl2/Ar, Cl2/N2/Ar, Cl2/H2/Ar, and Cl2/He/Ar. The authors found that nitrogen plays a significant role in fabricating high quality etched GaN nanostructures. This paper presents the effects of varying the etch parameters, including gas chemistry, gas flow rate, ICP power, rf power, chamber pressure, and substrate temperature, on the etch characteristics, including etch rate, sidewall angle, anisotropy, mask erosion, and surface roughness. Dominant etch mechanisms in relation to the observed characteristics of the etched features are discussed. Utilizing such methods, the authors demonstrated the fabrication of nanoscale...

Modified corrections for London forces in solid-state density functional theory calculations of structure and lattice dynamics of molecular crystals.

Dispersion forces are critical for defining the crystal structures and vibrational potentials of molecular crystals. It is, therefore, important to include corrections for these forces in periodic density functional theory (DFT) calculations of lattice vibrational frequencies. In this study, DFT was augmented with a correction term for London-type dispersion forces in the simulations of the structures and terahertz (THz) vibrational spectra of the dispersion-bound solids naphthalene and durene. The parameters of the correction term were modified to best reproduce the experimental crystal structures and THz spectra. It was found that the accurate reproduction of the lattice dimensions by adjusting the magnitude of the applied dispersion forces resulted in the highest-quality fit of the calculated vibrational modes with the observed THz absorptions. The method presented for the modification of the dispersion corrections provides a practical approach to accurately simulating the THz spectra of molecular crystals, accounting for inherent systematic errors imposed by computational and experimental factors.

Noncovalent Interactions between Modified Cytosine and Guanine DNA Base Pair Mimics Investigated by Terahertz Spectroscopy and Solid-State Density Functional Theory

Modified cytosine and guanine nucleobases cocrystallize in a hydrogen bonding configuration similar to that observed in native DNA. The noncovalent interactions binding these base pairs in the crystalline solid were investigated using terahertz (THz) spectroscopy and solid-state density functional theory (DFT). While stronger hydrogen bonding interactions are responsible for the general molecular orientations in the crystalline state, it is the weaker dipole-dipole and dispersion forces that determine the overall packing arrangement. The inclusion of dispersion interactions in the DFT calculations was found to be necessary to accurately simulate the unit cell structure and THz vibrational spectrum. Using properly modeled intermolecular potentials, the lattice vibrational motions of the cytosine and guanine derivatives were calculated. The vibrational characters of the modes exhibited by the DNA base pair mimic in the THz region were primarily rotational motions and are indicative of the energies and the nature of vibrations that would likely be observed between similar base pairs in DNA molecules.