Investigation of atropisomeric transformation of a novel PDE4 inhibitor with tetrahydroisoquinoline-based amide group and its primary study of binding to HSA.

In this study a kinetic and thermodynamic atropisomeric transformation due to a hindered rotation around the tetrahydroisoquinoline-based amide group was investigated. Quantum chemistry calculations were applied to investigate the transformation under the gas phase and several solvents with different polarity, and then evaluated by dynamic HPLC determination. It was found that the transformation rate of constants and the half-life time varied under the influence of solvent polarity and temperature and the energies of rotational barrier were determined ranging between 87 and 92 kJ∙mol-1. A primary binding study with HSA confirmed a rapid interconversion under the simulated physiological conditions. It is therefore suggested to take this atropisomeric compound as a racemic mixture for its future drug development.

Validated quantitative 31P NMR spectroscopy for positional isomeric impurity determination in L-α-glycerylphosphorylcholine (L-α-GPC).

In this study a quantitative 31P nuclear magnetic resonance (31P NMR) spectroscopy method was described to determine positional isomeric impurity ß-GPC in commercial products of L-α-GPC. The samples were dissolved in D2O and trimethyl phosphate (TMP) was selected as an internal calibrant. The measurements were performed on a Bruker 500 MHz spectrometer and the spectra were recorded under optimized process conditions. A good linear relationship was constructed for ß-GPC in the range of 62.7-528.0 µg·mL-1, i.e. 0.03-0.25 % (w/w %, in relative to L-α-GPC) with a correlative coefficient of 0.9996. The limit of quantification (LOQ) and limit of detection (LOD) were 62.7 µg·mL-1 and 20.9 µg·mL-1 with signal to noise of 3 and 10, respectively. The spiked recoveries were in the range of 98.17-99.78 % with the relative standard deviation (RSD %) less than 1.0 %. Therefore, it could be supposed that the 31P NMR was a promising alternative method for sensitive determination of ß-GPC for strict quality control of L-α-GPC.

Solvent polarity dependent ESIPT behavior for the novel flavonoid-based solvatofluorochromic chemosensors.

In this work, we explore the excited-state intramolecular proton transfer (ESIPT) mechanisms and relative solvent effects for three novel 3-hydroxylflavone derivatives (i.e., HOF, SHOF, and NSHOF) in acetonitrile, dichloromethane, and toluene solvents. Through calculations, we optimize the structures of HOF, SHOF, and NSHOF. Through the analysis of a series of structural parameters related to hydrogen bonding interactions, it could be found that the hydrogen bonds of the three derivatives are all enhanced in the S1 state, and more importantly, the excited-state hydrogen bonds of HOF are stronger than those of SHOF and NSHOF. In order to explore the effects of solvent polarity, we analyze the core-valence bifurcation (CVB) index, infrared (IR) vibration spectrum, and the potential energy curves. We find that for HOF, SHOF, and NSHOF, the strength of the excited-state hydrogen bonds increases as the solvent polarity decreases. The solvent polarity dependent ESIPT mechanisms pave the way for further designing novel flavonoid-based solvatofluorochromic probes in future.

Effects of azole rings with different chalcogen atoms on ESIPT behavior for benzochalcogenazolyl-substituted hydroxyfluorenes.

ESIPT behavior has attracted a lot of eyes of researchers in recent years because of its unique optical properties. Due to its large Stokes shift and double emission fluorescence, white light can be generated in the fluorophore based on the excited state intramolecular proton transfer (ESIPT) principle. The excited state proton transfer behavior of hydroxylated benzoxazole (BO-OH), benzothiazole (BS-OH) and benzoselenazole (BSe-OH) have been investigated in heptane, chloroform and DMF solvents. By comparing the infrared vibration spectra and the variation of bond parameters from the S0 to S1 states, and analyzing the frontier molecular orbitals, the influence of hydrogen bond dynamics, the solvent polarity, charge redistribution and the effects of different proton acceptors on proton transfer were observed. The only structural difference among the three substituted hydroxyfluorenes is the heteroatom in the azole ring (oxygen, sulfur and selenium, respectively). We have scanned the potential energy curve of the ESIPT process, and compared the potential barrier, it is found that the heavier chalcogen atoms are more favorable for proton transfer. At the same time, the potential application of changing heteroatoms in the azole ring by walking down the chalcogenic group in crystal luminescence color regulation is also discussed.

Dual fluorescence of 2-(2'-hydroxyphenyl) benzoxazole derivatives via the branched decays from the upper excited-state.

As a special fluorescence phenomenon, double fluorescence has been widely developed and applied in various fields. Nevertheless, most of the research on fluorescence emission channels focuses on the first excited state, while the research on how to control the fluorescence emission channel through the upper excited state is relatively under-explored. Here, we use the time-dependent density functional theory method and consider the 2-(2'-hydroxyphenyl) benzoxazole (HBO) derivative system as an example to study the effect of upper excited states on double fluorescence. According to the calculation results, a new mechanism for the dual fluorescence was proposed, which involved the different decay pathways from the upper excited-state, the internal conversion through vibrational relaxation, and conical intersection, respectively. This research has potential value and can help in determining how to control the fluorescence emission channel through the upper excited state.

Effects of Intermolecular Hydrogen Bonding and Solvation on Enol-Keto Tautomerism and Photophysics of Azomethine-BODIPY Dyads.

Boron-dipyrromethene derivatives (BODIPYs) are a category of molecules with excellent photophysical properties and can be applied to various fields. This work investigates the fluorescent properties of two azomethine-BODIPY dyads in different solvents based on the time-dependent density functional theory (TD-DFT) method. The potential energy curves (PECs) show that the polar protic solvent and the enhanced π-conjugation effect can lower the proton-transfer (PT) barriers, causing the main configuration of NA-BODIPY in methanol to be the keto form, while the main configuration of NA-BODIPY in toluene and SA-BODIPY in methanol and toluene is the enol form. The keto forms of the two compounds possess the twisted intramolecular charge transfer (TICT) decay pathway in the excited state identified by the optimized twisted configurations and the appropriate barriers of the TICT process, whereas the twisted configurations of the enol forms are nonexistent. TICT successfully competes with excited-state proton transfer (ESIPT) of the keto form, which leads to the fluorescence quenching of NA-BODIPY in methanol. This work provides new ideas for the influence of enol-keto tautomerism and the competitiveness of TICT and ESIPT on the photophysical properties of BODIPYs and is expected to provide guidance for the design of new BODIPY functional molecules.

[Advances on genotoxic impurities of sulfonate esters in pharmaceuticals].

This article reviews the refinement of regulatory guidelines and progress of research on the control of genotoxic impurities in pharmaceuticals in the last decade. It outlines advances in the regulatory requirements for genotoxic impurities from strict avoidance to the currently accepted concept of threshold of toxicological concern (TTC), which is based on risk control considerations. Specific control limits, which are required by predominant administrative regulatory agencies, such as U. S. Food and Drug Administration (FDA), European Medicines Agency (EMA) and the international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH), etc. Sulfonate esters, an important class of potential genotoxic impurities, are usually generated by side-reactions between sulfonic acids or their derivatives and relative low molecular mass alcohols, such as methanol, ethanol, and isopropanol. The resulting sulfonate esters are characterized with diverse chemical structures. Reaction mechanisms of the formation of sulfonate esters and various strategies to control them have been schematically described. A detailed summary has been given for the analytical methodology developed using high performance liquid chromatography (HPLC) and gas chromatography (GC) to determine trace amounts of sulfonate esters in pharmaceuticals. Furthermore, we have comprehensively discussed the options for the chromatographic methods, sample pretreatments, and derivatization methods, as well as each method's sensitivity and recovery at trace level. This review intended to provide constructive suggestions for the rational control of sulfonate esters in pharmaceuticals to ensure their clinical safety.

Trace determination of mutagenic alkyl toluenesulfonate impurities via derivatization headspace-GC/MS in an active pharmaceutical ingredient of a candidate drug.

This study aims to optimize sodium iodide (NaI) derivatization headspace-GC/MS described in European Pharmacopoeia by using vitamin C as an alternative antioxidant for the determination of mutagenic alkyl toluenesulfonate impurities in an active pharmaceutical ingredient (API) of a candidate drug with an artemisinin derivative. Alkyl toluenesulfonates are transformed into their corresponding alkyl iodides (methyl iodide, ethyl iodide, propyl iodide, and isopropyl iodide) by utilizing the derivatization reagent NaI. Results show that the MS response of methyl iodide is a critical indicator of method robustness because of the deteriorating effects of methyl iodide on stability when sodium thiosulfate is used as an antioxidant originally described in the pharmacopoeia. With vitamin C as a newly developed antioxidant, the robustness of this method is improved significantly. The optimized method is further validated and applied successfully for the quality control and safety of the API of an artemisinin derivative.