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.
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.
[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.
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.
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.
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.
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.
[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.
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.
[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.
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.
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.
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.
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.
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.
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.
[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
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.
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.
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.