44 research outputs found
Dabrafenib-Panobinostat Salt: Improving Dissolution Rate and Inhibition of BRAF Melanoma Cells
No full textCocrystallization of the drug−drug salt-cocrystal of the histone
deacetylase inhibitor (HDACi) panobinostat (PAN) and b-rapidly accelerated
fibrosarcoma (BRAF) inhibitor dabrafenib (DBF) afforded single crystals of a
two-drug salt stabilized by N+−H···O and N+−H···N− hydrogen bonds
between the ionized panobinostat ammonium donor and dabrafenib
sulfonamide anion acceptor in a 12-member ring motif. A faster dissolution
rate for both drugs was achieved through the salt combination compared to the
individual drugs in an aqueous acidic medium. The dissolution rate exhibited a
peak concentration (Cmax) of approximately 310 mg cm−2 min−1 for PAN and
240 mg cm−2 min−1 for DBF at a Tmax of less than 20 min under gastric pH 1.2
(0.1 N HCl) compared to the pure drug dissolution values of 10 and 80 mg
cm−2 min−1, respectively. The novel and fast-dissolving salt DBF−·PAN+ was
analyzed in BRAFV600E melanoma cells Sk-Mel28. DBF−·PAN+ reduced the
dose−response from micromolar to nanomolar concentrations and lowered IC50 (21.9 ± 7.2 nM) by half compared to PAN alone
(45.3 ± 12.0 nM). The enhanced dissolution and lower survival rate of melanoma cells show the potential of novel DBF−·PAN+ salt in clinical evaluation
Dramatically Enhanced Reactivity of Fullerenes and Tetrazine towards the Inverse-Electron-Demand Diels-Alder Reaction inside a Porous Porphyrinic Cage
No full textInverse-electron-demand Diels-Alder reaction (IEDDA) between fullerenes and 1,2,4,5-tetrazine generally requires harsh conditions and long reaction times due to their strong electron-accepting nature. Herein, we report a dramatic enhancement in the reactivity of the fullerenes (C-60/C-70)-tetrazine reaction inside a porous Zn-porphyrinic cage (Zn-PB) under sustainable conditions by installing a tetrazine-based axle (LA) via metal-ligand coordination bond, which modulates the cavity size to facilitate the encapsulation of fullerenes. Upon encapsulation, the close proximity of fullerenes and the tetrazine group of LA dramatically increase their reactivity towards the IEDDA reaction to form fullerene-tetrazine adducts. Furthermore, the C-60-tetrazine adduct is rearranged upon hydration to a bent-shaped C-60-pyrazoline adduct that can be released from the Zn-PB cavity in the presence of excess LA, thus catalyzing the formation of C-60-pyrazoline adduct inside Zn-PB without product inhibition.11Nsciescopu
Remotely controllable supramolecular rotor mounted inside a porphyrinic cage
No full text© 2021 Elsevier Inc.The confinement of molecular machines into nanostructured cages and controlling their functions by external stimuli holds great potential for the creation of smart functional materials that imitate the embodied intelligence of biological processes. Herein, we report the construction of a supramolecular rotor in a porous Zn-metallated porphyrinic cage (1) by encapsulation of a tetrazine-based linear axle (LA) via metal-ligand coordination bond, followed by post-assembly modification to append a controllable side arm to LA via inverse electron demand Diels-Alder (IEDDA) reaction. While the rotor alone shows nearly no motion, the addition of pyridine derivatives as a zinc coordinating ligand results in both 90° jump-like rotary motion of the rotor and slow tumbling motion of the rotor axle in a stochastic manner. Interestingly, the dual motions of the rotor can be reversibly controlled by the UV and visible light-induced coordination and dissociation of an azopyridine-based ligand with Zn centers as a signal transducer.11Nsciescopu
Recursive Anion-Triggered Tandem Reactions of ortho-Bis-ynones: Tunable Synthesis of 1Indenones and Cyclopenta[a]inden-8(2H)ones
No full textRecursive anion-mediated activation
of o-bis-ynones
sets off a Michael addition–aldol reaction–dehydrative
rearrangement cascade, leading to the one-pot synthesis of 1-indenones
via orthogonal interplay between the two ortho-ynone
moieties. Repeating the recursive anion engagement with the 1-indenones
unfolded access to a functionally embellished cyclopenta[a]inden-8(2H)-one core and its spiroannulated analogues
either directly or stepwise through tandem 1,6-Michael-type addition–6π
electrocyclization and an in situ oxidation sequence
Novel Hydrate and Anhydrate Cocrystals/Salts of Norfloxacin and Their Physicochemical Properties
No full textThe low solubility and low permeability of Biopharmaceutics
Classification
System BCS class IV antibiotic drug norfloxacin (NORF) were studied
for improvement of physicochemical properties in hydrated and anhydrous
cocrystals/salts of NORF with methyl paraben (MBZ), ethyl
paraben, methanesulfonic acid (MSA), benzenesulfonic acid (BSA), p-toluenesulfonic
acid (PTSA), and tyramine (TYM). These crystalline forms were characterized
by powder X-ray diffraction (PXRD), thermal [differential scanning
calorimetry (DSC)], gravimetric [thermogravimetric analysis (TGA)],
spectroscopic [infrared (IR)], and microscopy [scanning electron microscopy
(SEM)] techniques. The crystal structures of NORF-MBZ-HYD, NORF-MSA-HYD,
NORF-PTSA, and NORF-TYM-HYD were analyzed by single-crystal X-ray
diffraction. Further, the hydrated and anhydrous forms were characterized
by IR, DSC, and TGA to understand the hydration and dehydration events
and by field emission SEM for crystal morphology and shape/size characteristics.
Solubility, dissolution, and diffusion measurements showed that NORF
anhydrous forms are more soluble and diffusible than their corresponding
hydrated forms. Notably, NORF ionic crystal forms with MSA and BSA
are highly soluble with good dissolution rates and high cumulative
drug diffusion
High-Solubility Salts of the Multiple Sclerosis Drug Teriflunomide
No full textTeriflunomide (TFM) is
an immunomodulatory prodrug of leflunomide which is used for the treatment
of multiple sclerosis (MS). It is a Biopharmaceutics Classification
System Class (BCS) II drug with low solubility and high permeability.
The X-ray crystal structure of TFM is stabilized by O–H···O,
C–H···O, C–H···N, and
N–H···N interactions. In order to study the
solubility and dissolution changes of this drug, five multicomponent
crystal forms were prepared with amine and amide generally regarded
as safe (GRAS) coformers to improve the physicochemical properties
such as solubility, dissolution, diffusion, and phase stability. Equimolar
TFM–coformer 1:1 salts were crystallized, except for cytosine
which afforded a salt cocrystal toluene solvate TFM–CYT–TOL
in a 1:2:1 ratio. The multicomponent forms were crystallized by slow
solvent evaporation and characterized by single crystal X-ray diffraction.
TFM and coformer are bonded by N+–H···O–, N–H···O, O–H···O,
C–H···O, C–H···N, N–H···N,
and C–H···F interactions. The bulk phase purity
of the salts was characterized by powder X-ray diffraction and infrared
and thermal techniques. Solubility, dissolution, and diffusion experiments
in pH 7.0 buffer exhibited a significant improvement compared to the
reference drug. The morphology and particle size of salts by field
emission scanning electron microscopy were related to dissolution
behavior. The highest solubility, dissolution, and diffusion profile
were observed for TFM–MEA and TFM–TEA salts (monoethanol
amine and triethanol amine)
Salts and Salt Cocrystals of the Antibacterial Drug Pefloxacin
No full textPefloxacin (PEF)
is an amphoteric, antibacterial drug which exists
as a neutral molecule in the crystal structure stabilized by C–H···O
and C–H···F interactions. The design of multicomponent
solids using crystal engineering was undertaken in a cocrystal/salt
screen of PEF with generally recognized as safe (GRAS) dicarboxylic
acids to improve the solubility and phase stability of the drug. Ten
multicomponent forms, namely, five salts, two salt hydrates, and three
salt cocrystals, were prepared by liquid-assisted grinding followed
by crystallization. In some cases, salt and salt cocrystals were obtained
concomitantly during solution evaporative crystallization. Single
crystal X-ray diffraction showed that the structures are stabilized
by N+–H···O–, O–H···O,
C–H···O, C–H···F, and
π–π stacking interactions. The bulk phase purity
of multicomponent forms was characterized by powder X-ray diffraction,
spectroscopy, and thermal techniques. The salt/salt cocrystal forms
exhibit a faster dissolution rate and higher solubility compared to
pure PEF in pH 1.2 (acidic, like gastric environment) and pH 7 phosphate
buffer media (neutral, like intestinal passage). Specifically the
PEF+–SA– salt (SA = succinic acid)
showed remarkably high solubility, dissolution rate, and stability
compared to the other multicomponent forms and PEF neutral form. The
drug formulation compatible pefloxacin succinate is a promising soluble
and stable PEF salt
Crystal engineering of a zwitterionic drug to neutral cocrystals: a general solution for floxacins
No full textThe transformation of zwitterionic Sparfloxacin (SPX) to the neutral form is achieved by cocrystallization. Neutral forms of drugs are important for higher membrane permeability, while zwitterions are more soluble in water. The twin advantages of higher solubility/dissolution rate and good stability of neutral SPX are achieved in a molecular cocrystal compared to its zwitterionic SPX hydrate. The amine-phenol supra-molecular synthon drives cocrystal formation, with the paraben ester acting as a ``proton migrator'' for the ionic to neutral transformation
