Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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  • 73 巻 (2025) 3 号 p. 213-226
    Evaluation of Time-Dependent Deformation Behavior of Pharmaceutical Excipients in the Tableting Process もっと読む
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    In this manuscript, the authors investigate the time-dependent deformation behavior of powdered or granular materials during tableting using a compaction simulator. Four pharmaceutical excipients with different compression characteristics were analyzed using a trapezoidal punch displacement profile, where only the punch speed during loading was varied. By evaluating strain rate sensitivity, mechanical energy, and stress relaxation, differences in deformation behavior between the materials were identified. The results suggest that an accurate understanding of the time-dependent deformation characteristics of raw materials is important to support appropriate scale-up of the tableting process.

  • 73 巻 (2025) 3 号 p. 234-245
    Highly Precise Anomaly Detection Using Multivariate Statistical Process Control with Appropriate Scaling of Input Variables in Pharmaceutical Continuous Manufacturing もっと読む
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    Multivariate statistical process control (MSPC) has attracted considerable attention as a monitoring method for pharmaceutical continuous manufacturing. However, there are few examples of its application in pharmaceutical manufacturing, and previous studies have shown high false positive rates. In this study, the authors proposed a method to improve the accuracy of anomaly detection using MSPC by determining the appropriate scaling factor used for standardization and applied it to the granulation and drying processes in pharmaceutical continuous manufacturing. The proposed method reduces the false positive rate compared to conventional methods and can detect changes in process parameters and raw materials.

  • 73 巻 (2025) 3 号 p. 246-256
    Structure–Signal Relationships of the δ-Opioid-Receptor (DOR)-Selective Agonist KNT-127—Part I: Impact of the Morphinan Skeleton on the G-Protein-Biased DOR Agonism もっと読む
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    [Highlighted Paper selected by Editor-in-Chief]
    The δ-opioid receptor (DOR) is a promising therapeutic target with reduced side effects compared to μ-opioid receptor agonists. However, some DOR agonists, such as SNC80, have been reported to induce convulsions, potentially involving β-arrestin signaling. This study investigates the first structure–signal relationship of KNT-127, a morphinan-based DOR agonist, and demonstrates that the morphinan skeleton reduces β-arrestin recruitment, while the quinoline moiety modulates the bias between G protein and β-arrestin pathways. These findings expand the classical message–address concept and offer valuable insights into the rational design of functionally selective DOR agonists with improved safety profiles.

  • 73 巻 (2025) 3 号 p. 264-267
    Concise and Highly Stereoselective Synthesis of β,β-Disubstituted α,β-Unsaturated Esters もっと読む
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    β,β-Disubstituted α,β-unsaturated carbonyl compounds, which are characterized by two distinct substituents at the β-position, are found in various bioactive molecules. In this paper, the authors report a concise and highly stereoselective synthesis method for β,β-disubstituted α,β-unsaturated esters. This synthesis method comprises three well-known reactions: the aldol reaction of acetic ester derivatives with ketones, the acetylation of tert-alcohols, and an elimination reaction utilizing DBU. Two important findings, i.e., that the acetylation of bulky tert-alcohol proceeded efficiently using Ac2O and DMAP without DBU as a base, and that the formation of isomerized byproducts in the elimination reaction was suppressed by removing excess DMAP, enabled the synthesis of various β,β-disubstituted α,β-unsaturated esters.

  • 73 巻 (2025) 2 号 p. 86-93
    Stereoselective Synthesis of Aromatic Polyketide Prealnumycin もっと読む
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    The alnumycin-class antibiotics constitute a polyketide-derived benzoisochromanequinone core hybridized with a structurally rearranged D-ribose. In this article, the authors reported the stereoselective synthesis and absolute configuration of prealnumycin, the aglycon of alnumycin. The key transformation involves the highly diastereoselective introduction of an n-propyl group onto a tricyclic lactone via nucleophilic addition, followed by silane reduction. Subsequent regioselective arene oxidation to naphthoquinone, acidic deprotection, and dehydration afford prealnumycin in eight steps. The findings from this synthesis provide insights into the total synthesis of this class of natural products.

  • 73 巻 (2025) 2 号 p. 94-102
    Novel Vial-Inner-Surface Treatment Technology Improves Chemical Durability and Vial-Inner-Surface Uniformity to Reduce Drug Adsorption on the Vial もっと読む
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    The authors developed potential injection glass vials by using the novel vial-inner-surface treatment (VIST) technology to homogenize the inner surface of the vials. Compared with those of common vials, the elution of alkali contents and conductivity of these injection glass vials were reduced because of the VIST technology resulting in the formation of smooth and homogeneous inner surfaces of the vials. In addition, drug adsorption onto the inner surface of the VIST vials was considerably lowered than that onto common vials. These results suggest that VIST vials are of excellent quality and could become the standard injection glass vials.

  • 73 巻 (2025) 2 号 p. 103-107
    Design, Synthesis, and Characterization of 1-(Anthracen-9-ylmethyl)-1,5,9-triazacyclododecane (Ant-[12]aneN3) and Its DNA Photocleavage Activity もっと読む
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    In this manuscript, the authors described the design and synthesis of a derivative of 1,5,9-triazacyclododecane ([12]aneN3) bearing an anthracen-9-ylmethyl moiety (Ant-[12]aneN3) and evaluated its DNA cleavage activity under UV irradiation at 365 nm. They found that its DNA cleavage activity was dependent on UV irradiation but not on the presence of zinc ions, despite the expectation that the [12]aneN3 moiety would facilitate DNA cleavage through zinc ion chelation. The authors also investigated the DNA cleavage activity of Ant-[12]aneN3 in comparison to structurally related compounds and elucidated the unique role of the [12]aneN3 moiety in Ant-[12]aneN3 in DNA cleavage. This work would contribute to the field of cyclic polyamines and the photoreactivity of the anthracene moiety.

  • 73 巻 (2025) 2 号 p. 121-135
    Ion-Pair Extraction with Tetracyanocyclopentadienides: A Method for Estimating Extraction Efficiency もっと読む
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    [Highlighted Paper selected by Editor-in-Chief]
    Quaternary ammonium cations are difficult to handle in organic chemistry owing to their ionic nature. Ion-pair extraction is commonly adopted for isolating quaternary ammonium cations; however, predictions of extraction efficiency are often based on researchers’ intuition. In this study, the authors derived an equation to predict the extraction efficiency of ammonium–tetracyanocyclopentadienide ion pairs. The prediction equation involves the CLOGP values of ammonium and lipophilic constants of anions and is also applicable to ion-pair extraction with many common anions. These findings will aid the development of future studies using ammonium cations as synthetic substrates and products.

  • 73 巻 (2025) 1 号 p. 18-24
    Comparative Analysis of Needleless and Needle-Based Electrospinning Methods for Polyamide 6: A Technical Note もっと読む
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    This study compares needleless and needle-based electrospinning methods for producing polyamide 6 (PA6) nanofibers, emphasizing fiber diameter and solvent effects. The needleless method produced thicker fibers, with the largest diameters obtained using a 2:1 acetic acid: formic acid solvent system. While the needle-based method provides better control over fiber morphology, the needleless technique enables higher production rates, making it more viable for industrial applications. The findings highlight the need for further optimization to enhance PA6 nanofibers’ suitability for pharmaceutical and biomedical uses, including drug delivery and wound dressing applications.

  • 73 巻 (2025) 1 号 p. 25-38
    Synthesis and Structure–Activity Relationships of Novel Benzofuran Derivatives with Osteoblast Differentiation-Promoting Activity もっと読む
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    [Highlighted Paper selected by Editor-in-Chief]
    The authors synthesized a novel series of 3,5-disubstituted benzofuran derivatives with osteoblastogenic activities and investigated their structure–activity relationships. Compound 23d, which contained a substituent with a tetrahydropyranyl group used in previously reported diphenylether derivatives, exhibited lower activity, but higher oral absorbability, resulting in similar osteogenic effects to diphenylether derivatives in ovariectomized female rats. These effects were mediated by the inhibition of cyclin-dependent kinase 8. Therefore, 3,5-disubstituted benzofuran is a useful scaffold for orally active osteogenic agents, and 23d is a potential candidate for a novel anti-osteoporotic drug.

  • 73 巻 (2025) 1 号 p. 39-45
    Preparation of a Stable Indomethacin Supersaturated Solution Using Hydrophobically Modified Hydroxypropylmethylcellulose and α-Cyclodextrin もっと読む
    編集者のコメント

    Amorphous solid dispersions (ASDs) have garnered significant interest for enhancing the oral bioavailability of poorly water-soluble drugs by generating supersaturated drug concentrations. The stabilization of drug supersaturation critically depends on the structure–property–performance relationships of polymers employed. However, the development of such polymers using economical and practical methods remains challenging. In this study, the authors demonstrated that a highly supersaturated state of indomethacin (IM) can be maintained through a combination of hydrophobically modified hydroxypropylmethylcellulose (HM-HPMC) and α-cyclodextrin (α-CD). α-CD alters the association state of HM-HPMC by forming inclusion complexes with its stearyl moieties, thereby enhancing the stability of IM supersaturation. The combined use of HM-HPMC and α-CD represents a promising and simple strategy for modulating polymer properties and improving the oral bioavailability of poorly water-soluble drugs in ASD formulations.

  • 73 巻 (2025) 1 号 p. 46-57
    Toward the Synthesis of Strychnos Alkaloids: Effective Construction of Fused Cyclohexane and Pyrrolidine Portion of the Strychnos Skeleton via Domino Intermolecular and Intramolecular SN2 Cyclization もっと読む
    編集者のコメント

    Strychnos alkaloids, represented by strychnine, have a fused 5-6-6 ring system containing a nitrogen atom and an indoline portion known as the strychnos skeleton. In this manuscript, the authors describe the development of an effective method for constructing the fused cyclohexane and pyrrolidine portion of the strychnos skeleton using domino cycliza­tion as a key step. Thus, cyclization precursors that have a tosylate group as a secondary leaving group on the ring were treated with NsNH2 and K2CO3 in DMF to afford fused cyclohexane and pyrrolidine com­pounds without an E2 elimination product. This reaction is easy to conduct and yields pyrrolidine in good yield.

  • 73 巻 (2025) 1 号 p. 58-62
    In-Situ Monitoring of Dissolution and Crystallization Processes of Carbamazepine Using Low-Frequency Raman Spectroscopy and Multivariate Analysis もっと読む
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    Crystal polymorph is a key quality attribute of solid state active pharmaceutical ingredients. Authors successfully monitored the crystal polymorphs of carbamazepine during the dissolution and crystallization processes by using low-frequency (LF) Raman spectroscopy. The research is the first application of multivariate analysis on LF Raman spectra to quantitate undissolved crystal polymorphs of carbamazepine during these processes. Calibration models, developed using partial least squares regression, showed good correlation between actual and predicted values, indicating the model’s accuracy in quantitation. It is suggested that LF Raman spectroscopy can serve as a useful tool for process analytical technology.

  • 72 巻 (2024) 12 号 p. 1043-1047
    Synthetic Studies of Javaberine A Based on Intramolecular Hydroamination of Alkenes もっと読む
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    This study presents the total synthesis of javaberine A, a bioactive berberine alkaloid, via a lithium amide-mediated intramolecular hydroamination of N-allylamines. By optimizing reagent ratios, the authors successfully controlled the reaction pathways, producing either the desired monocyclized product leading to javaberine A or an unexpected tricyclic product. Furthermore, they developed a method to epimerize the H8-H14 cis-benzyl tetrahydroisoquinoline into its trans isomer via β-elimination followed by hydroamination. This work not only advances synthetic strategies for javaberine A but also provides valuable insights into controlling stereoselectivity in berberine alkaloid synthesis.

  • 72 巻 (2024) 12 号 p. 1055-1060
    Colloidal Particle in Suspensions of Maobushisaishinto Extract Granules Enhances Drug Intestinal Penetration もっと読む
    編集者のコメント

    Maobushisaishinto (MBST), which is Kampo preparation, has been used to treat the common cold, and nasal allergy in Japan. However, it is still unclear in what proportions these dispersions are obtained when the Kampo preparation is suspended, and their absorption in different dispersions. Authors investigated what type of dispersions in MBST-based suspensions. In conclusion, the authors found that the coarse-, colloidal- and molecular-dispersions are produced when MBST are suspended. Moreover, the authors also showed that colloidal particles in suspension enhanced the absorption of main ingredients of MBST. These findings provide valuable insights into the optimal administration of Kampo preparations.

  • 72 巻 (2024) 12 号 p. 1061-1064
    Long-Range Halogen Dance Reaction in 4,5-Dihalogeno-2-(Sulfur-Containing Heterocyclyl)thiazole もっと読む
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    This study presents a new type of halogen dance reaction in halogenated bithiazole and (thienyl)thiazole derivatives. In contrast to typical halogen dance reactions, which are 1,2- or 1,3-halogen shifts around the ring, in their reaction the bromine or iodine group moves to a long-range position beyond the ring. The authors demonstrated several combinations of halogen donors and acceptors to achieve long-range halogen dance reactions. They also found that the neighboring group participation of the thiazole group affects the regioselectivity. This method will be a powerful tool for the synthesis of functionalized thiazole derivatives.

  • 72 巻 (2024) 12 号 p. 1084-1104
    A Novel Series of Coumarin Derivatives That Exert Osteoblastogenic Effects in Mesenchymal Stem Cells and Osteogenic Effects in Ovariectomized Female Rats もっと読む
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    [Highlighted Paper selected by Editor-in-Chief]
    Osteoporosis is treated with oral and parenteral resorption inhibitors and parenteral osteogenic drugs. Orally active small-molecule osteogenic drugs have been long desired. In the article, the authors synthesized a novel series of 4,6-substituted coumarin derivatives and found that compounds 11m and 29v showed osteoblastogenic activities by inhibition of CDK8, and cortical bone selective osteogenic effects in femoral metaphysis and diaphysis with increases in plasma bone-type ALP activity in micro-computed tomography analyses of ovariectomized female rats. The 4,6-substituted coumarin structures are useful scaffolds for osteoblastogenic compounds, and 11m and 29v have potential as orally active anti-osteoporotic agents

  • 72 巻 (2024) 12 号 p. 1110-1115
    Structures of Polyacetoxybriaranes Extracted from the Sea Whip Octocoral Junceella fragilis もっと読む
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    The algae-associated sea whip octocoral Junceella fragilis, recognized as a medicinal marine invertebrate, underwent chemical screening. This analysis led to the isolation of six notable polyacetoxybriaranes, including a new compound identified as fragilide Z. The structures of the known compounds were determined using single-crystal X-ray diffraction analysis, while the structure of the new compound was elucidated through two-dimensional nuclear magnetic resonance (NMR) analysis. Notably, all the compounds demonstrated activity in promoting the growth of MG-63 human mesenchymal stem cells.

  • 72 巻 (2024) 11 号 p. 961-965
    Correlation between Membrane Permeability and the Intracellular Degradation Activity of Proteolysis-Targeting Chimeras もっと読む
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    This study examines the relationship between membrane permeability and the intracellular degradation activity of Proteolysis-Targeting Chimeras (PROTACs). Using hematopoietic prostaglandin D synthase (H-PGDS) as a model protein, this study investigated how linker length impacts the performance of PROTACs. The findings reveal that membrane permeability and H-PGDS degradation activity are influenced by linker properties, with shorter linkers shown to enhance both permeability and activity under specific conditions. This study highlights the importance of linker optimization in PROTAC design and provides strategies to balance molecular weight, permeability, and efficacy. These insights contribute to the advancement of PROTACs as effective therapeutic agents.

  • 72 巻 (2024) 11 号 p. 966-969
    Synthetic Study towards Providencin: Stereocontrolled Synthesis of the Furan-Substituted Cyclobutanol Segment もっと読む
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    Providencin, a marine diterpenoid with a unique structure featuring two furan and oxirane rings along with a bicyclo[12.2.0]hexadecane skeleton, has attracted interest as a potential lead compound for drug development. The authors successfully synthesized its challenging right-half segment, a furan-substituted cyclobutane, in 10 steps. Notable advances include the [2+2] cycloaddition of lithium ynolates to construct a poly-substituted cyclobutene, followed by stereoselective hydrogenation using Crabtree’s catalyst. This streamlined approach represents a major milestone in the synthesis of multi-functional cyclobutanes and represents a significant step forward in total synthesis research.

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