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⁺–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

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