Abstract The essence of developing multicomponent solid formulations for drugs with poor physicochemical and pharmacokinetic properties is rapidly evolving to cut short the consumption of resources and time. Quite a few commercially available binary drug formulations in the public domain serve as a prime illustration of the field’s success. However, the design and utilization of ternary or higher-order drug formulations can be more efficacious in terms of enhancing such properties of the drug as well as providing humidity resistance and controlling unexpected phase transitions during drug development. Low-soluble and low-permeable BCS IV class drugs continuously present a barrier by lowering their absorption in the body. Drugs mesalamine (MSA) and acetazolamide (ACZ) from the same BCS class were chosen to enhance properties by introducing the binary and ternary solid formulation approach. Soluble and acceptable co-partners, viz., vitamin B6 (pyridoxine hydrochloride, PRDHCl) and p-Aminobenzoic acid (PABA), were carefully chosen. The grinding of MSA and ACZ with p-aminobenzoic acid (PABA) resulted in a physical mixture (MSA·PABA) and a cocrystal (ACZ·PABA), respectively, due to the mismatch of functional moieties and shape. Interestingly, the addition of PRDHCl to the two binary systems generated two ternary eutectic solids, viz., PRDHCl·MSA·PABA and PRDHCl·ACZ·PABA. The thermal and spectroscopic analyses suggested that PRDHCl·MSA·PABA is a mixture of PRDHCl, MSA and PABA. However, PRDHCl·ACZ·PABA exists as a combination of the cocrystal ACZ·PABA and PRDHCl. The conversion of different binary solids to ternary eutectic solids showed a notable impact on the pH-dependent solubility and membrane permeability of both drugs, MSA and ACZ. Microenvironmental pH (MpH) and different microspecies (neutral, ionic, and zwitterionic) generated at the solid−liquid interface are accountable for the altered and improved pH-dependent solubility and membrane permeability of the solids.
Abstract Solvate formation in molecular crystals remains difficult to predict, particularly under non-equilibrium conditions, where the initial solid state, mechanically generated surfaces, anisotropic surface chemistry, and solvent properties collectively influence solid-solvent interactions. While mechanochemical processing is widely used to access new solid forms, the structural features that control solvent incorporation during mechanical activation are not yet well understood. In this work, we investigate mechanochemically induced solvate formation in ivacaftor as a model molecular crystal, focusing on the effects of solvent nature, liquid-additive volume, milling duration, and starting solid form. Form C transformed selectively to a solvate, in MeOH, THF, and DMSO, whereas the amorphous material exhibited broader solvate-forming behavior, including hydrate and non-polar solvate formation. The observed transformations could not be explained by solvent class or apparent dissolution capacity alone, demonstrating the importance of the starting solid state and specific host-solvent interactions. Crystal structure and surface analyses of form C identified the (200) plane as a plausible mechanically responsive plane whose alternative termination exposes polar groups involved in the resulting solvate structures. Overall, the results support a model in which mechanochemical solvate formation is governed by the interplay among the initial solid state, mechanically generated surfaces, and specific solid-solvent interactions.
Abstract The stereoregular organosilicon ligand, all-trans-tetra(p-carboxyphenyl)-cyclotetrasiloxane (H4A), was utilized as a novel building block for the construction of the HOF and coordination polymers (CPs/MOFs). Strong hydrogen bonding and dense 3-fold interpenetration in the H4A-HOF determined the high thermal and solvolytic stability of H4A. H4A and M(II) form novel crystalline CPs/MOFs in pyridine-containing media under ambient (in Pyr/H2O, B−F) and solvothermal (in Pyr/DMF, G) conditions. Pyridine plays a crucial role in the formation and stabilization of B−G, facilitating the dissolution of H4A and shaping the coordination environment of M(II). Cd(II)- (B), Zn(II)/Cd(II)- (C), and Co(II)-based (D) products are structurally similar 1D CPs/MOFs of the 2,4C4 topology. Hg(II)- (F) and Cd(II)-based (G) products are structurally similar 2D CPs/MOFs of the sql topology. The influence of solvent inclusion and hydrogen bonding on the CP/MOF aperture size was shown using the example of B−D. The influence of the initial reagent phase distribution and mixing order was demonstrated by the growth of 1D and 2D Co(II)-based CPs/MOFs D and E (hcb topology). If the dissolution of H4A is hindered, the templated formation of E with an inherited large aperture organization (∼52 × 18 Å) occurs. Structural analysis confirms the flexible nature of the ligand and similar organization patterns of the crystals, thus highlighting the usability of H4A for the CP/MOF design and the preparation of functional materials in the future.
Abstract Cocrystals offer promising approaches for the targeted regulation of raw material properties. Nevertheless, the accurate screening of cocrystal co-formers remains a critical bottleneck in the rational preparation of cocrystals. To address this challenge, a cocrystal prediction model based on multimodal fusion was constructed by integrating molecular descriptors, fingerprints, SMILES strings and molecular graphs to screen potential co-formers. The model incorporates a dynamic attention fusion mechanism and a tailored data-balancing strategy to address unimodal limitations and class imbalance, thereby enhancing classification performance under the present evaluation framework. It demonstrated strong classification performance and outperformed the evaluated unimodal models. Diosmetin was selected as the model compound, and systematic virtual screening identified promising co-formers, leading to the successful synthesis of diosmetin-4,4′-bipyridine and diosmetin-isonicotinamide cocrystals. Structural characterization revealed a 2:1 supramolecular network of diosmetin-4,4′-bipyridine stabilized by O−H···N hydrogen bonds. The two cocrystals showed lower moisture uptake than diosmetin under the tested high-humidity conditions of 40 °C/75% RH and 40 °C/95% RH. This study presents a multimodal fusion strategy for cocrystal prediction and highlights its potential in the rational design of solid forms.
Abstract Kagomé compounds have attracted great interest in materials science and condensed matter physics owing to their unique structures and rich exotic magnetic phenomena. In this work, starting from the nonmagnetic kagomé lattice compound KV5+3(SeO3)2O6, we successfully obtained a new kagomé compound KV3(SeO3)2O3F3 by introducing F− ions to tune the valence state of vanadium. This compound crystallizes in the trigonal space group R-3m, featuring a regular S = 1/2 kagomé layer composed of V4+ ions. Magnetic and heat capacity measurements reveal a long-range ferromagnetic order below ∼3.1 K.
