No abstract

The discovery of molecular ionic cocrystals (ICCs) of active pharmaceutical ingredients (APIs) widens the opportunities for optimizing the physicochemical properties of APIs whilst facilitating the delivery of multiple therapeutic agents. However, ICCs are often observed serendipitously in crystallization screens and the factors dictating their crystallization are poorly understood. We demonstrate here that mechanochemical ball milling is a versatile technique for the reproducible synthesis of ternary molecular ICCs in less than 30 min of grinding with or without solvent. Computational crystal structure prediction (CSP) calculations have been performed on ternary molecular ICCs for the first time and the observed crystal structures of all the ICCs were correctly predicted. Periodic dispersion‐corrected DFT calculations revealed that all the ICCs are thermodynamically stable (mean stabilization energy=−2 kJ mol−1) relative to the crystallization of a physical mixture of the binary salt and acid. The results suggest that a combined mechanosynthesis and CSP approach could be used to target the synthesis of higher‐order molecular ICCs with functional properties.

Over the past 2 decades, significant progress has been made in developing a robust supramolecular toolkit for the crystal engineering of simple binary cocrystals. By contrast, crystal engineering of higher-order molecular ionic cocrystals (ICCs) is not well established. Here, we report the results of the most extensive survey of the molecular and crystal properties of ICCs reported to date and use the resulting data to propose a set of guiding principles to aid the crystallization of molecular ICCs sustained by charge-assisted hydrogen bonding interactions. Using a data set comprising a total of 94 ICC crystal structures, this work reveals that molecular ICCs are favored within a narrow range of the property landscape. Specifically, most of the ICCs in the data set are crystallized using molecules with significantly different polar surface areas. The data also highlight the importance of choosing molecules with a similar number of conformational degrees of freedom when targeting higher-order cocrystals. Molecular ICCs comprising conjugate acid–base fragments are more likely to be observed in crystallization screens when the difference in the ionization constants of the acid–base pair lie within the “gray” zone of the salt–cocrystal continuum. This work also reveals the hierarchy in the supramolecular heterosynthons of molecular ICCs. Finally, periodic dispersion-corrected density functional theory calculations on a limited subset of crystal structures reveals that most of the ICCs surveyed are driven to form on the basis of favorable energetics as indicated by a mean stabilization energy of −5 kJ mol–1.

Derivatives of polycyclic aromatic hydrocarbons (PAHs) are widely used in optoelectronic materials. However, the poor solubility of unfunctionalized PAHs represents a challenge for the continued application of these compounds in emerging technologies. For organic compounds bearing one or more functional groups capable of engaging in directional hydrogen or halogen-bonding interactions, the crystal engineering toolkit currently offers many routes for optimizing the solid-state properties of these compounds. Such efforts typically lead to the discovery of periodic crystal forms that display strong adhesive intermolecular forces between the molecular fragments. By contrast, the crystal engineering of organic eutectic composites is relatively unexplored and poorly understood. Here, we report the mechanosynthesis and experimental characterization of the properties of three eutectic composites of pyrene (PYR) and anthracene (ANTH) that were discovered using the coformer bisphenol A (BPA) or phenothiazine (PTZ). The resulting eutectic composites (PYR-BPA, PYR-PTZ, and ANTH-PTZ) display significant melting point depressions ranging from 19 to 51 °C relative to the melting point of the PAH. The equilibrium solubilities of the composite materials were also observed to be 2−5 times greater than that of the PAH. The crystal engineering of eutectic solid forms is currently hampered by the lack of reliable empirical or theoretical tools for predicting their formation. A weighted Monte Carlo simulation was used to estimate the mixing energies and binding modes of a limited set of molecular pairs, leading to temperature-dependent interaction parameters that show promise in the selection of coformers with a high likelihood of forming eutectic composites. Complementary dispersion-corrected density functional theory (DFT-D) calculations on a set of PYR and ANTH composite models reveal that organic eutectic composites are not driven to form on the basis of favorable thermodynamics as evidenced by an average interaction energy of 2.60 kJ mol −1 across the series. Synthon incompatibility and molecular shape mismatch appear to be important factors to consider in targeting eutectic solid forms. This work paves the way for the systematic crystal engineering of organic eutectic solid forms with tunable physicochemical properties using a synergistic computational modeling and mechanosynthesis approach.

Previous studies on biocatalytic transformations of pinenes by cytochrome P450 (CYP) enzymes reveal the formation of different oxygenated products from a single substrate due to the multistate reactivity of CYP and the many reactive sites in the pinene scaffold. Up until now, the detailed mechanism of these biocatalytic transformations of pinenes have not been reported. Hereby, we report a systematic theoretical study of the plausible hydrogen abstraction and hydroxylation reactions of α- and β-pinenes by CYP using the density functional theory (DFT) method. All DFT calculations in this study were based on B3LYP/LAN computational methodology using the Gaussian09 software. We used the B3LYP functional with corrections for dispersive forces, BSSE, and anharmonicity to study the mechanism and thermodynamic properties of these reactions using a bare model (without CYP) and a pinene-CYP model. According to the potential energy surface and Boltzmann distribution for radical conformers, the major reaction products of CYP-catalyzed hydrogen abstraction from β-pinene are the doublet trans (53.4%) and doublet cis (46.1%) radical conformer at delta site. The formation of doublet cis/trans hydroxylated products released a total Gibbs free energy of about 48 kcal/mol. As for alpha pinene, the most stable radicals were trans-doublet (86.4%) and cis-doublet (13.6%) at epsilon sites, and their hydroxylation products released a total of ~50 kcal/mol Gibbs free energy. Our results highlight the likely C-H abstraction and oxygen rebounding sites accounting for the multi-state of CYP (doublet, quartet, and sextet spin states) and the formation of different conformers due to the presence of cis/trans allylic hydrogen in α-pinene and β-pinene molecules.