Evaluation of the OPLS-AA Force Field for the Study of Structural and Energetic Aspects of Molecular Organic Crystals

Motivated by the need for reliable experimental data for the assessment of theoretical predictions, this work proposes a data set of enthalpies of sublimation determined for specific crystalline structures, for the validation of molecular force fields (FF). The selected data were used to explore the ability of the OPLS-AA parametrization to investigate the properties of solid materials in molecular dynamics simulations. Furthermore, several approaches to improve this parametrization were also considered. These modifications consisted in replacing the original FF atomic point charges (APC), by values calculated using quantum chemical methods, and by the implementation of a polarizable FF. The obtained results indicated that, in general, the best agreement between theoretical and experimental data is found when the OPLS-AA force field is used with the original APC or when these are replaced by ChelpG charges, computed at the MP2/aug-cc-pVDZ level of theory, for isolated molecules in the gaseous phase. If a good description of the energetic relations between the polymorphs of a compound is required then either the use of polarizable FF or the use of charges determined taking into account the vicinity of the molecules in the crystal (combining the ChelpG and MP2/cc-pVDZ methods) is recommended. Finally, it was concluded that density functional theory methods, like B3LYP or B3PW91, are not advisable for the evaluation of APC of organic compounds for molecular dynamic simulations. Instead, the MP2 method should be considered

Evaluation of the OPLS-AA Force Field for the Study of Structural and Energetic Aspects of Molecular Organic Crystals

Motivated by the need for reliable experimental data for the assessment of theoretical predictions, this work proposes a data set of enthalpies of sublimation determined for specific crystalline structures, for the validation of molecular force fields (FF). The selected data were used to explore the ability of the OPLS-AA parametrization to investigate the properties of solid materials in molecular dynamics simulations. Furthermore, several approaches to improve this parametrization were also considered. These modifications consisted in replacing the original FF atomic point charges (APC), by values calculated using quantum chemical methods, and by the implementation of a polarizable FF. The obtained results indicated that, in general, the best agreement between theoretical and experimental data is found when the OPLS-AA force field is used with the original APC or when these are replaced by ChelpG charges, computed at the MP2/aug-cc-pVDZ level of theory, for isolated molecules in the gaseous phase. If a good description of the energetic relations between the polymorphs of a compound is required then either the use of polarizable FF or the use of charges determined taking into account the vicinity of the molecules in the crystal (combining the ChelpG and MP2/cc-pVDZ methods) is recommended. Finally, it was concluded that density functional theory methods, like B3LYP or B3PW91, are not advisable for the evaluation of APC of organic compounds for molecular dynamic simulations. Instead, the MP2 method should be considered

Modeling Halogen Bonds in Ionic Liquids: A Force Field for Imidazolium and Halo-Imidazolium Derivatives

In this work, a force field for molecular dynamics and Monte Carlo simulations of ionic liquids containing imidazolium and halo-imidazolium derivatives is presented. This force field is an extension of the well-known CL&P and OPLS-AA models and was validated by comparing predicted crystalline structures for 22 ionic liquid compounds with the corresponding data deposited at the Cambridge Structural Database. The obtained results indicate that the proposed force field extension allows the reproduction of the crystal data with an absolute average deviation lower than 2.4%. Finally, it was also established that the halogen atoms covalently bound to the studied imidazolium cations are positively charged and do not exhibit a so-called σ-hole feature. For this reason, the formation of halogen bonds in the proposed force field appears naturally from the parametrized atomic point-charge distribution, without the necessity of any extra interaction sites

Polymorphism in 4‑Hydroxybenzaldehyde: A Crystal Packing and Thermodynamic Study

A procedure for the selective and reproducible preparation of the two known 4-hydroxybezaldehyde polymorphs was developed, based on the investigation of their relative stabilities by differential scanning calorimetry and solubility studies. From the obtained results, the stability domains of the two forms could be quantitatively represented in a Δ_f<i>G</i>_m^°–<i>T</i> phase diagram. The system was found to be enantiotropic: form II is more stable than form I up to 277 ± 1 K; above this temperature, the stability order is reversed, and the fusion of form I subsequently occurs at 389.9 ± 0.2 K. Analysis of the crystal structures revealed that in both polymorphs the 4-hydroxybezaldehyde molecule exhibits the OH and C­(O)H substituents in a <i>Z</i> conformation, which, according to B3LYP/6-31G­(d,p) calculations, is more stable than the <i>E</i> conformation by only 0.4 kJ·mol^–1. The two forms are monoclinic, space group <i>P</i>2₁/<i>c</i>, <i>Z</i>′/<i>Z</i> = 1/4, and have essentially identical densities at ambient temperature (1.358 g·cm^–3 for form I; 1.357 g·cm^–3 for form II), but differ in their packing. These differences are discussed, and the dissimilarities in the interactions sustaining the packing are highlighted using Hirshfeld surfaces. Finally, the relative stability and volumetric properties of both forms are analyzed by molecular dynamics simulations

All-Atom Force Field for Molecular Dynamics Simulations on Organotransition Metal Solids and Liquids. Application to M(CO)_<i>n</i> (M = Cr, Fe, Ni, Mo, Ru, or W) Compounds

A previously developed OPLS-based all-atom force field for organometallic compounds was extended to a series of first-, second-, and third-row transition metals based on the study of M­(CO)<i>_n</i> (M = Cr, Fe, Ni, Mo, Ru, or W) complexes. For materials that are solid at ambient temperature and pressure (M = Cr, Mo, W) the validation of the force field was based on reported structural data and on the standard molar enthalpies of sublimation at 298.15 K, experimentally determined by Calvet-drop microcalorimetry using samples corresponding to a specific and well-characterized crystalline phase: Δ_sub<i>H</i>_m^° = 72.6 ± 0.3 kJ·mol^–1 for Cr­(CO)₆, 73.4 ± 0.3 kJ·mol^–1 for Mo­(CO)₆, and 77.8 ± 0.3 kJ·mol^–1 for W­(CO)₆. For liquids, where problems of polymorphism or phase mixtures are absent, critically analyzed literature data were used. The force field was able to reproduce the volumetric properties of the test set (density and unit cell volume) with an average deviations smaller than 2% and the experimentally determined enthalpies of sublimation and vaporization with an accuracy better than 2.3 kJ·mol^–1. The Lennard-Jones (12-6) potential function parameters used to calculate the repulsive and dispersion contributions of the metals within the framework of the force field were found to be transferable between chromium, iron, and nickel (first row) and between molybdenum and ruthenium (second row)

From Molecules to Crystals: The Solvent Plays an Active Role Throughout the Nucleation Pathway of Molecular Organic Crystals

Crystallization is indisputably one of the oldest and most widely used purification methods. Despite this fact, our current understanding of the early stages of crystallization is still in its infancy. In this work dynamic light scattering and proton nuclear magnetic resonance were used to investigate the changes occurring in 4′-hydroxyacetophenone colloidal particles, as they form in a supersaturated aqueous solution and evolve toward anhydrous or hydrate materials during a cooling crystallization process. In the concentration range probed, the particles are initially composed by both solute and water. If the outcome of crystallization is an anhydrous phase, a complete loss of solvent from the particles is progressively observed up to the onset of crystal precipitation. These findings provide unique experimental evidence that the role of solvent in the formation of crystals can go well beyond influencing the self-assembly and clustering of solute molecules prior to nucleation

Energetics and Structure of Simvastatin

The study of structure–energetics relationships for active pharmaceutical ingredients has received considerable attention in recent years, due to its importance for the effective production and safe use of drugs. In this work the widely prescribed cholesterol-lowering drug simvastatin was investigated by combining experimental (combustion calorimetry and differential scanning calorimetry, DSC) and computational chemistry (quantum chemistry and molecular dynamics calculations) results. The studies addressed the crystalline form stable at ambient temperature (form I) and the liquid and gaseous phases. Heat capacity determinations by DSC showed no evidence of polymorphism between 293 K and the fusion temperature. It was also found that the most stable molecular conformation in the gas phase given by the quantum chemistry calculations (B3LYP-D3/cc-pVTZ) is analogous to that observed in the crystal phase. The molecular dynamics simulations correctly captured the main structural properties of the crystalline phase known from published single crystal X-ray diffraction results (unit cell dimensions and volume). They also suggested that, while preferential conformations are exhibited by the molecule in the solid at 298.15 K, these preferences are essentially blurred upon melting. Finally, the experiments and calculations led to enthalpies of formation of simvastatin at 298.15 K, in the crystalline (form I) Δ_f<i>H</i>_m^o(cr I) = −1238.4 ± 5.6 kJ·mol^–1, liquid Δ_f<i>H</i>_m^o(l) = −1226.4 ± 5.7 kJ·mol^–1, and gaseous Δ_f<i>H</i>_m^o(g) = −1063.0 ± 7.1 kJ·mol^–1 states

Polymorphic Phase Transition in 4′-Hydroxyacetophenone: Equilibrium Temperature, Kinetic Barrier, and the Relative Stability of <i>Z</i>′ = 1 and <i>Z</i>′ = 2 Forms

Particularly relevant in the context of polymorphism is understanding how structural, thermodynamic, and kinetic factors dictate the stability domains of polymorphs, their tendency to interconvert through phase transitions, or their possibility to exist in metastable states. These three aspects were investigated here for two 4′-hydroxyacetophenone (HAP) polymorphs, differing in crystal system, space group, and number and conformation of molecules in the asymmetric unit. The results led to a Δ_f<i>G</i>_m°-<i>T</i> phase diagram highlighting the enantiotropic nature of the system and the fact that the <i>Z</i>′ = 1 polymorph is not necessarily more stable than its <i>Z</i>′ = 2 counterpart. It was also shown that the form II → form I transition is entropy driven and is likely to occur through a nucleation and growth mechanism, which does not involve intermediate phases, and is characterized by a high activation energy. Finally, although it has been noted that conflicts between hydrogen bond formation and close packing are usually behind exceptions from the hypothesis of <i>Z</i>′ = 1 forms being more stable than their higher <i>Z</i>′ analogues, in this case, the HAP polymorph with stronger hydrogen bonds (<i>Z</i>′ = 2) is also the one with higher density

A New Thermodynamically Favored Flubendazole/Maleic Acid Binary Crystal Form: Structure, Energetics, and <i>in Silico</i> PBPK Model-Based Investigation

The use of flubendazole (FBZ) in the treatment of lymphatic filariasis and onchocerciasis (two high incidence neglected tropical diseases) has been hampered by its poor aqueous solubility. A material consisting of binary flubendazole/maleic acid crystals (FBZ/MA), showing considerably improved solubility and dissolution rate relative to flubendazole alone, has been prepared in this work through solvent assisted mechanical grinding. The identification of FBZ/MA as a binary crystalline compound with salt character (proton transfer from MA to FBZ) relied on the combined results of powder X-ray diffraction, Raman spectroscopy, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), thermogravimetry (TG), and differential scanning calorimetry (DSC). Isothermal solution microcalorimetry studies further suggested that the direct formation of FBZ/MA from its precursors in the solid state is thermodynamically favored. A comparison of the <i>in silico</i> pharmacokinetic performance of the FBZ/MA with that of pure FBZ based on a rat fasted physiology model indicated that the absorption rate, mean plasma peak concentration, and absorption extension of FBZ/MA were ∼2.6 times, ∼1.4 times, and 60% larger, respectively, than those of FBZ. The results here obtained therefore suggest that the new FBZ/MA salt has a considerable potential for the development of stable and affordable pharmaceutical formulations with improved dissolution and pharmacokinetic properties. Finally, powder X-ray diffraction studies also led to the first determination of the crystal structure of FBZ