In pharmaceutical development, synthesizing active pharmaceutical ingredients (APIs) for small-molecule and macromolecular compounds has become increasingly challenging. Many APIs under development do not have optimal solubility, membrane permeability, or stability, substantially complicating formulation or rendering it impossible. Ionic liquids (ILs) have attracted attention in the pharmaceutical field because their chemical structures can be tailored. Moreover, ILs have simple preparation processes and afford high solubility and chemical and thermal stability. However, the use of conventional ILs in pharmaceutical development is limited owing to concerns about biocompatibility, toxicity, and environmental impact. Therefore, in response to these challenges, greater focus has been placed on developing biocompatible ILs, in which both the cation and anion are composed of components that are biologically compatible and/or capable of reducing the environmental burden. This review focuses on ILs developed from biologically related components, especially biocompatible ILs derived from choline and amino acids. Furthermore, it discusses their use in pharmaceuticals, such as catalysts for API synthesis, crystallization, improving solubility, enhancement of skin permeation, designing oral formulations, antibacterial agents, and protectants for macromolecules. Additionally, this review explores how converting APIs into ILs with choline or amino acids can improve their physicochemical properties.

Deep eutectic solvents (DESs) are liquids formed by mixing two or more solid components, typically hydrogen bond donors and acceptors, resulting in a large decrease in melting point. Since DESs were first reported in 2003, they have attracted growing attention owing to their low cost, tunable physicochemical properties, and potential environmental compatibility. In pharmaceutical sciences, DESs are increasingly being explored as alternative solvents and functional media for active pharmaceutical ingredient (API) development. This review outlines recent advances in the use of DESs in pharmaceutical research, focusing on the solubilization of poorly water-soluble APIs and the formation of multicomponent crystals. DESs can increase API solubility greatly compared with water, in some cases by several orders of magnitude. In addition, DESs can also be used as crystallization media and coformer sources, enabling the preparation of salts and cocrystals without conventional organic solvents. The effects of DES composition, viscosity, and water content on solubility, crystallization behavior, and processability are also discussed. Although challenges, such as high viscosity and separation of products, remain several mitigation strategies including dilution, additive use and solvent recycling have been proposed. Overall, DESs are a promising platform for innovative, sustainable API development.

Ionic liquids (ILs) have garnered significant attention in pharmaceutical development because of their diverse applications in improving drug absorption across the nasal mucosa. However, because ILs typically exhibit high viscosity, their poor spray characteristics through intranasal devices pose a challenge for their intranasal administration. To address this issue, we designed an intranasal powder formulation that can be applied using an intranasal powder device by loading an IL within the pores of mesoporous silica (MPS). MPS was added to an IL composed of choline and L-malic acid, and the mixture was stirred. Over time, IR spectroscopy measurements revealed a reduction in the intensity of the IL-derived peaks, suggesting that most ILs were associated with MPS pores. This loading process proceeded more rapidly at higher mixing temperatures owing to the reduced IL viscosity. Furthermore, specific surface area measurements and scanning electron microscopy (SEM) observations demonstrated that the IL was successfully encapsulated within the pores with minimal residue on the MPS surface at an MPS:IL mixing ratio of 1 : 0.4. The IL-MPS prepared from MPS with different physical properties tended to exhibit improved flowability compared to the original MPS, suggesting that the amount of IL retained may vary with the MPS pore volume. The spray characteristics of the IL-MPSs prepared using an intranasal powder device were superior to those of lactose hydrate, a commonly used excipient. Thus, the IL-MPS powder formulation can be a suitable candidate for intranasal administration.

Three new C₂₀ quassinoids, eurycomanoic acids A–C (1–3), were isolated from a 70% MeOH extract of the roots of Eurycoma longifolia Jack (Simaroubaceae), collected in Malaysia. Their structures were elucidated based on extensive spectroscopic analyses, including one-dimensional (1D) and 2D-NMR, IR, and UV spectroscopy, and high-resolution electrospray ionization mass spectrometry. Compounds 1–3 have a tetrahydrofuran ring in the D-ring moiety, bearing a carboxy group and a hydroxy group at C-15. The stereochemistry at C-15 of 1–3 was determined to be S by comparing the total energies of the most stable conformers of both C-15 epimers, obtained from density functional theory calculations. Eurycomanoic acid A (1) may be biosynthesized from 15β-hydroxyklaineanone (4) via 15-oxoklaineanone.

Trichodermamides D–F were isolated in 2017, along with known trichodermamides A–C, from the mangrove-derived endophytic fungus Penicillium janthinellum. Although the pronounced bioactivities of trichodermamides A–C, including cytotoxic and antimicrobial activities, have been reported, the bioactivities of trichodermamides D–F have not yet been determined. The absence of reported lethal activity prompted us to focus on nonlethal biological targets and to conduct enzymatic and phenotypic screening aimed at identifying antivirulence activity. On the other hand, we recently developed a scalable, chiral-pool-based asymmetric synthesis of the trichodermamides A–F. Using this synthetic platform, 11 natural and unnatural enantiomers of trichodermamides D–F, along with selected synthetic intermediates, were evaluated to elucidate structure–activity relationships. This broad screening effort identified that the unnatural enantiomer of trichodermamide F exhibited selective inhibitory activity against the bacterial type III secretion system (T3SS), with an IC₅₀ of 76.7 μM, while showing no antibacterial activity. This study revealed the first trichodermamide derivative that targets the nonlethal T3SS, highlighting the importance of considering unnatural enantiomers and demonstrating the untapped antivirulence potential of the trichodermamide scaffold.

We previously developed an intracellular carrier, an aminated polyrotaxane (amino-PRX), that recognizes and deforms in response to the shape and charge distribution of proteins and nucleic acids. Amino-PRX can deliver various biopharmaceuticals into cells with high efficiency. However, the detailed intracellular behavior of the carrier alone and its complexes in the cells remains unclear. In addition, the usefulness of amino-PRX as a carrier for introducing antibodies into cells is unclear. In this study, we prepared fluorescently capped amino-PRX to visualize the intracellular distribution of the carrier, drugs, and the complexes. Moreover, not only the fluorescence of the carrier and drug themselves within cells but also Förster resonance energy transfer (FRET)-derived fluorescence between the two components was observed to examine the intracellular behavior of the complex. First, fluorescently capped PRX was prepared by capping polypseudorotaxane, consisting of α-cyclodextrin (α-CyD) and polyethylene glycol (2 or 20 kDa), with 5(6)-carboxyfluorescein (FAM). Next, diethylenetriamine (DET) was modified onto the α-CyD of PRX to obtain amino-PRX, namely, DET-PRX_-FAM (2 or 20 kDa). In HeLa cells, DET-PRX_-FAM (2 kDa) exhibited lower cytotoxicity compared to DET-PRX_-FAM (20 kDa). Importantly, FRET-derived fluorescence was observed upon adding DET-PRX_-FAM (2 kDa) to phycocyanin or HiLyte Fluor™ 647-modified human immunoglobulin G due to complex formation. Moreover, fluorescence from the carrier, proteins, and FRET, derived from the complex, was observed in HeLa cells. These results suggest the successful construction of a fluorescent molecular-capped amino-PRX that enables visualization of the intracellular distribution of the carrier, drugs, and the complexes.

This study investigated the rheological behavior of nanosuspensions prepared by a wet media milling technique using various model drugs and hydroxypropyl methylcellulose (HPMC) as a dispersing agent. These nanosuspensions were classified into two groups based on their apparent fluidity: the first included fenofibrate, glimepiride, and phenytoin nanosuspensions, which maintained high fluidity and exhibited Newtonian-like behavior (yield stress <0.09 Pa in the Herschel–Bulkley model); and the second comprised griseofulvin, ketoconazole, and nevirapine nanosuspensions, which showed markedly reduced fluidity and non-Newtonian characteristics (yield stress >1.7 Pa in the Herschel–Bulkley model). Quantitative analysis of HPMC adsorption showed a tendency for drugs with high HPMC adsorption (11.2–12.4 wt%) to demonstrate high fluidity, while drugs with low HPMC adsorption (8.14–8.86 wt%) generally showed reduced fluidity. Notably, fenofibrate remained flowable despite relatively low HPMC adsorption, underscoring that the adsorption amount alone is not sufficient to explain fluidity and that adsorption mode and coverage may also contribute. Rheological analysis under heating conditions revealed that all nanosuspensions exhibited a temperature-dependent rheological transition at temperatures lower than those typically reported for pure HPMC solutions. A reduction in fluidity was observed when this transition occurred below room temperature. Together, these results indicate that drug-dependent fluidity loss in wet-milled nanosuspensions is associated with differences in interfacial HPMC association and temperature-dependent structuring, involving both hydrophobic nanoparticle network formation and HPMC molecular assembly.

Gelatin is an attractive wall material for microcapsule fabrication because it enables solvent-free processing. However, conventional gelatin microcapsules typically require chemical crosslinkers for structural stabilization, which may raise safety concerns and compromise the bioactivity of encapsulated protein therapeutics or antigens. Herein, we report a crosslinker-free method for fabricating gelatin microcapsules via twin-fluid spray-droplet atomization using a full-cone nozzle. Gelatin microcapsules loaded with ovalbumin (OVA), a model protein (antigen), were successfully prepared without chemical crosslinking, and the encapsulated antigen retained its in vivo antigenicity, indicating that its biological function was preserved.

Coumarin and its derivatives exhibit diverse biological activities and have extensive applications in biomedicine. A series of coumarin derivatives (1–15) were designed and synthesized, among which eight compounds had not been reported previously. In particular, single crystals of compounds 8 and 10 were obtained and characterized by X-ray diffraction, which provided a molecular basis for analyzing their antioxidant activity. The antioxidant properties were evaluated through ‧OH scavenging assays, cyclic voltammetry (CV) assays, redox potential measurements, oxygen radical absorbance capacity (ORAC) tests, and in vivo reactive oxygen species (ROS) scavenging experiments using Caenorhabditis elegans (C. elegans). At the same time, density functional theory (DFT) calculations were also conducted to assist in the study of the antioxidant mechanism. IC₅₀ values for ·OH scavenging were significantly lower than those of the positive control, vitamin C. Furthermore, ORAC assays showed moderate to excellent scavenging ability (with Trolox equivalents of 1.08 for compound 13). CV assays assessed the abilities to scavenge ‧O₂⁻, with results consistent with ORAC experimental findings. In vivo antioxidant activities were further investigated using C. elegans. Finally, through multiple free-radical scavenging experiments and DFT calculations, the antioxidant mechanism of the compounds was elucidated. In conclusion, through structural modification and the comparison of activities, profound insights were obtained. This work thereby established both a theoretical framework and an experimental basis for the rational design of new antioxidants.

A practical synthesis of mirabegron, a first-line drug for the treatment of overactive bladder, was developed. This synthetic route avoids the use of structural alerts such as aniline and nitrobenzene, which raise concerns regarding human exposure during large-scale synthesis. This strategy relies on the Cu-catalyzed coupling between an aryl halide and an amide derivative, which was successfully conducted on a gram scale by selecting a suitable diamine ligand and an appropriate protecting group for the amine.

Three-component coupling reactions involving aldehydes, amines, and either resorcinols or indoles are described. Substituted benzylamine derivatives were synthesized in water at room temperature. The reaction was initiated by dehydration of an aldehyde and amine, followed by arylation of the resulting imine to produce the three-component coupling product. This reaction process does not require any catalyst or promoter. The co-product is a water molecule, and the reaction proceeds under environmentally friendly conditions at room temperature in water. Substituted N-alkyl-1-(resorcinol)alkylamines and 2-arylglycines were effectively obtained in a one-pot reaction.