Predicting crystal form stability under real-world conditions.

The physicochemical properties of molecular crystals, such as solubility, stability, compactability, melting behaviour and bioavailability, depend on their crystal form1. In silico crystal form selection has recently come much closer to realization because of the development of accurate and affordable free-energy calculations2-4. Here we redefine the state of the art, primarily by improving the accuracy of free-energy calculations, constructing a reliable experimental benchmark for solid-solid free-energy differences, quantifying statistical errors for the computed free energies and placing both hydrate crystal structures of different stoichiometries and anhydrate crystal structures on the same energy landscape, with defined error bars, as a function of temperature and relative humidity. The calculated free energies have standard errors of 1-2 kJ mol-1 for industrially relevant compounds, and the method to place crystal structures with different hydrate stoichiometries on the same energy landscape can be extended to other multi-component systems, including solvates. These contributions reduce the gap between the needs of the experimentalist and the capabilities of modern computational tools, transforming crystal structure prediction into a more reliable and actionable procedure that can be used in combination with experimental evidence to direct crystal form selection and establish control5.

Self-Assembled Monolayers Get Their Final Finish via a Quasi-Langmuir-Blodgett Transfer.

The growth of self-assembled monolayers (SAMs) of octadecylphosphonic acid (ODPA) molecules on α-Al2O3(0001) and subsequent dewetting of the SAMs were studied with a combination of in situ sum-frequency generation (SFG) and molecular dynamics (MD) simulations. Although SAM growth after deposition times >8 h reduces to nearly negligible values, the resultant ODPA SAMs in solution are still not in a well-ordered state with the alkyl chains in all-trans configurations. In fact, in situ SFG spectroscopy revealed a comparatively high concentration of gauche defects of the SAM in the ODPA 2-propanol solution even after a growth time of 16 h. Here, results of the MD simulations strongly suggest that defects can be caused by ODPA molecules which are not attached to the substrate but are incorporated into the SAM layer with the polar headgroup oriented into the 2-propanol solvent. This inverted adsorption geometry of additional ODPA molecules blocks adsorption sites and thus stabilizes the SAM without improving ordering to an extent that all molecules are in the all-trans configuration. While persistent in solution, the observed defects can be healed out when the SAMs are transferred from the solvent to a gas phase. During this process, a quasi-Langmuir-Blodgett transfer of molecules takes place which drives the SAM into a higher conformational state and significantly improves its quality.

Indentation and self-healing mechanisms of a self-assembled monolayer--a combined experimental and modeling study.

A combination of in situ vibrational sum-frequency generation (SFG) spectroscopy and molecular-dynamics (MD) simulations has allowed us to study the effects of indentation of self-assembled octadecylphosphonic acid (ODPA) monolayers on α-Al2O3(0001). Stress-induced changes in the vibrational signatures of C-H stretching vibrations in SFG spectra and the results of MD simulations provide clear evidence for an increase in gauche-defect density in the monolayer as a response to indentation. A stress-dependent analysis indicates that the defect density reaches saturation at approximately 155 MPa. After stress is released, the MD simulations show an almost instantaneous healing of pressure-induced defects in good agreement with experimental results. The lateral extent of the contact areas was studied with colocalized SFG spectroscopy and compared to theoretical predictions for pressure gradients from Hertzian contact theory. SFG experiments reveal a gradual increase in gauche-defect density with pressure before saturation close to the contact center. Furthermore, our MD simulations show a spatial anisotropy of pressure-induced effects within ODPA domains: molecules tilted in the direction of the pressure gradient increase in tilt angle while those on the opposite side form gauche-defects.

Improving the charge transport in self-assembled monolayer field-effect transistors: from theory to devices.

A three-pronged approach has been used to design rational improvements in self-assembled monolayer field-effect transistors: classical molecular dynamics (MD) simulations to investigate atomistic structure, large-scale quantum mechanical (QM) calculations for electronic properties, and device fabrication and characterization as the ultimate goal. The MD simulations reveal the effect of using two-component monolayers to achieve intact dielectric insulating layers and a well-defined semiconductor channel. The QM calculations identify improved conduction paths in the monolayers that consist of an optimum mixing ratio of the components. These results have been used both to confirm the predictions of the calculations and to optimize real devices. Monolayers were characterized with X-ray reflectivity measurements and by electronic characterization of complete devices.

Efficient Crystal Structure Prediction for Structurally Related Molecules with Accurate and Transferable Tailor-Made Force Fields.

Crystal structure prediction (CSP) is generally used to complement experimental solid form screening and applied to individual molecules in drug development. The fast development of algorithms and computing resources offers the opportunity to use CSP earlier and for a broader range of applications in the drug design cycle. This study presents a novel paradigm of CSP specifically designed for structurally related molecules, referred to as Quick-CSP. The approach prioritizes more accurate physics through robust and transferable tailor-made force fields (TMFFs), such that significant efficiency gains are achieved through the reduction of expensive ab initio calculations. The accuracy of the TMFF is increased by the introduction of electrostatic multipoles, and the fragment-based force field parameterization scheme is demonstrated to be transferable for a family of chemically related molecules. The protocol is benchmarked with structurally related compounds from the Bromodomain and Extraterminal (BET) domain inhibitors series. A new convergence criterion is introduced that aims at performing only as many ab initio optimizations of crystal structures as required to locate the bottom of the crystal energy landscape within a user-defined accuracy. The overall approach provides significant cost savings ranging from three- to eight-fold less than the full-CSP workflow. The reported advancements expand the scope and utility of the underlying CSP building blocks as well as their novel reassembly to other applications earlier in the drug design cycle to guide molecule design and selection.

Improving the Performance of Organic Thin-Film Transistors by Ion Doping of Ethylene-Glycol-Based Self-Assembled Monolayer Hybrid Dielectrics.

Tuning the electrostatics of ethylene-glycol-based self-assembled monolayers (SAMs) by doping with ions is shown. Molecular dynamics simulations unravel binding mechanisms and predict dipole strengths of the doped layers. Additionally, by applying such layers as dielectrics in organic thin-film transistors, the incorporated ions are proven to enhance device performance by lowering the threshold voltage and increasing conductivity.