6 research outputs found
Crystal engineering of a zwitterionic drug to neutral cocrystals: a general solution for floxacins
The 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
Dabrafenib-Panobinostat Salt: Improving Dissolution Rate and Inhibition of BRAF Melanoma Cells
Cocrystallization 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
Salts and Salt Cocrystals of the Antibacterial Drug Pefloxacin
Pefloxacin (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<sup>+</sup>–H···O<sup>–</sup>, 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<sup>+</sup>–SA<sup>–</sup> 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
Dramatically Enhanced Reactivity of Fullerenes and Tetrazine towards the Inverse-Electron-Demand Diels–Alder Reaction inside a Porous Porphyrinic Cage
© 2022 Wiley-VCH GmbH.Inverse-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 (C60/C70)-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 C60-tetrazine adduct is rearranged upon hydration to a bent-shaped C60-pyrazoline adduct that can be released from the Zn-PB cavity in the presence of excess LA, thus catalyzing the formation of C60-pyrazoline adduct inside Zn-PB without product inhibition.11Nsciescopu
Dramatically Enhanced Reactivity of Fullerenes and Tetrazine towards the Inverse-Electron-Demand Diels-Alder Reaction inside a Porous Porphyrinic Cage
Inverse-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
© 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