Non-flammable Gel Polymer Electrolyte for Enhancing the Safety and High-Temperature Performance of Lithium-Ion Batteries.

As the applications of lithium-ion batteries (LIBs) have expanded, battery safety has emerged as a major concern because of the thermal runaway of LIBs arising from the use of flammable liquid electrolytes (LEs). Gel polymer electrolytes (GPEs) have been considered as potential candidates to replace LEs and improve the thermal safety of LIBs. In our study, a chemically cross-linked nonflammable GPE was synthesized and used in an LIB. A cross-linking agent, spirocyclic pentaerythritol diphosphate perfluorinated ether acrylate, comprising a phosphorus moiety and a fluoroether chain, was designed and synthesized to prepare a nonflammable cross-linked GPE. The obtained GPE effectively suppressed the deleterious reactions of the LE and imparted nonflammable characteristics. The pouch-type graphite/LiNi0.6Co0.2Mn0.2O2 cell with a nonflammable GPE delivered an initial discharge capacity of 146.7 mAh g-1 with a capacity retention of 71.1% after 300 cycles at 0.5 C and 55 °C. Moreover, the chemically cross-linked GPE exhibited excellent dimensional and thermal stability, which allowed for the safer operation of LIBs even under harsh conditions. This work provides guidelines for designing nonflammable electrolyte systems for advanced LIBs with high safety, enhanced thermal stability, and good cycling characteristics at elevated temperatures.

Cathode Electrolyte Interphase-Forming Additive for Improving Cycling Performance and Thermal Stability of Ni-Rich LiNixCoyMn1-x-yO2 Cathode Materials.

High-capacity Ni-rich LiNixCoyMn1-x-yO2 (NCM) has been investigated as a promising cathode active material for improving the energy density of lithium-ion batteries (LIBs); however, its practical application is limited by its structural instability and low thermal stability. In this study, we synthesized tetrakis(methacryloyloxyethyl)pyrophosphate (TMAEPPi) as a cathode electrolyte interphase (CEI) additive to enhance the cycling characteristics and thermal stability of the LiNi0.8Co0.1Mn0.1O2 (NCM811) material. TMAEPPi was oxidized to form a uniform Li+-ion-conductive CEI on the cathode surface during initial cycles. A lithium-ion cell (graphite/NCM811) employing a liquid electrolyte containing 0.5 wt % TMAEPPi exhibited superior capacity retention (82.2% after 300 cycles at a 1.0 C rate) and enhanced high-rate performance compared with the cell using a baseline liquid electrolyte. The TMAEPPi-derived CEI layer on NCM811 suppressed electrolyte decomposition and reduced the microcracking of the NCM811 particles. Our results reveal that TMAEPPi is a promising additive for forming stable CEIs and thereby improving the cycling performance and thermal stability of LIBs employing high-capacity NCM cathode materials.

Enhancing Dissolution and Oral Bioavailability of Ursodeoxycholic Acid with a Spray-Dried pH-Modified Extended Release Formulation.

Ursodeoxycholate (UDCA) has low oral bioavailability and pH-dependent solubility and permeability. Thus, we developed a pH-modified extended-release formulation of UDCA using Na2CO3 as the alkalizing agent and hydroxypropyl methylcellulose (HPMC) as the release-modifying agent. The optimized pH-modified controlled-release UDCA formulation, with the UDCA:HPMC:Na2CO3 ratio of 200:600:150 (w/w/w), was prepared using a spray-drying method. Then, the formulation's solubility, dissolution, and pharmacokinetic properties were characterized. In a pH-modified extended-release formulation of UDCA, the solubility of UDCA was increased to 8 mg/mL with a sustained dissolution for 12 h. Additionally, the spray-dried formulation exhibited amorphous states without molecular interaction among UDCA, Na2CO3, and HPMC. Moreover, the plasma UDCA concentration of the formulation maintained a higher UDCA concentration for up to 48 h than that of UDCA itself or the non-extended-release UDCA formulation. Consequently, the formulation significantly increased the AUC compared to UDCA or the non-extended-release UDCA formulation in rats. In conclusion, we have improved UDCA's solubility and dissolution profile by preparing a pH-modified extended-release formulation with the UDCA:HPMC:Na2CO3 ratio of 200:600:150 (w/w/w), which effectively increased the oral bioavailability of UDCA by 251% in rats.

Effect of Lactic Acid Bacteria on the Pharmacokinetics and Metabolism of Ginsenosides in Mice.

This study aims to investigate the effect of lactic acid bacteria (LAB) on in vitro and in vivo metabolism and the pharmacokinetics of ginsenosides in mice. When the in vitro fermentation test of RGE with LAB was carried out, protopanaxadiol (PPD) and protopanaxadiol (PPD), which are final metabolites of ginsenosides but not contained in RGE, were greatly increased. Compound K (CK), ginsenoside Rh1 (GRh1), and GRg3 also increased by about 30%. Other ginsenosides with a sugar number of more than 2 showed a gradual decrease by fermentation with LAB for 7 days, suggesting the involvement of LAB in the deglycosylation of ginsenosides. Incubation of single ginsenoside with LAB produced GRg3, CK, and PPD with the highest formation rate and GRd, GRh2, and GF with the lower rate among PPD-type ginsenosides. Among PPT-type ginsenosides, GRh1 and PPT had the highest formation rate. The amoxicillin pretreatment (20 mg/kg/day, twice a day for 3 days) resulted in a significant decrease in the fecal recovery of CK, PPD, and PPT through the blockade of deglycosylation of ginsenosides after single oral administrations of RGE (2 g/kg) in mice. The plasma concentrations of CK, PPD, and PPT were not detectable without change in GRb1, GRb2, and GRc in this group. LAB supplementation (1 billion CFU/2 g/kg/day for 1 week) after the amoxicillin treatment in mice restored the ginsenoside metabolism and the plasma concentrations of ginsenosides to the control level. In conclusion, the alterations in the gut microbiota environment could change the ginsenoside metabolism and plasma concentrations of ginsenosides. Therefore, the supplementation of LAB with oral administrations of RGE would help increase plasma concentrations of deglycosylated ginsenosides such as CK, PPD, and PPT.

Improved Hygroscopicity and Bioavailability of Solid Dispersion of Red Ginseng Extract with Silicon Dioxide.

This study aims to develop a powder formulation for the Korean red ginseng extract (RGE) and to evaluate its in vitro and in vivo formulation characteristics. The solid dispersion of RGE was prepared with hydrophilic carriers using a freeze-drying method. After conducting the water sorption-desorption isothermogram (relative humidity between 30 and 70% RH), differential scanning calorimetry thermal behavior, dissolution test, and intestinal permeation study, a solid dispersion formulation of RGE and silicon dioxide (RGE-SiO2) was selected. RGE-SiO2 formulation increased intestinal permeability of ginsenoside Rb1 (GRb1), GRb2, GRc, and GRd by 1.6-fold in rat jejunal segments as measured by the Ussing chamber system. A 1.6- to 1.8-fold increase in plasma exposure of GRb1, GRb2, GRc, and GRd in rats was observed following oral administration of RGE-SiO2 (375 mg/kg as RGE). No significant difference was observed in the time to reach maximum concentration (Tmax) and half-life in comparison to those in RGE administered rats (375 mg/kg). In conclusion, formulating solid dispersion of RGE with amorphous SiO2, the powder formulation of RGE was successfully formulated with improved hygroscopicity, increased intestinal permeability, and enhanced oral bioavailability and is therefore suitable for processing solid formulations of RGE product.

Involvement of Organic Anion Transporters in the Pharmacokinetics and Drug Interaction of Rosmarinic Acid.

We investigated the involvement of drug transporters in the pharmacokinetics of rosmarinic acid in rats as well as the transporter-mediated drug interaction potential of rosmarinic acid in HEK293 cells overexpressing clinically important solute carrier transporters and also in rats. Intravenously injected rosmarinic acid showed bi-exponential decay and unchanged rosmarinic acid was mainly eliminated by urinary excretion, suggesting the involvement of transporters in its renal excretion. Rosmarinic acid showed organic anion transporter (OAT)1-mediated active transport with a Km of 26.5 µM and a Vmax of 69.0 pmol/min in HEK293 cells overexpressing OAT1, and the plasma concentrations of rosmarinic acid were increased by the co-injection of probenecid because of decreased renal excretion due to OAT1 inhibition. Rosmarinic acid inhibited the transport activities of OAT1, OAT3, organic anion transporting polypeptide (OATP)1B1, and OATP1B3 with IC50 values of 60.6 µM, 1.52 µM, 74.8 µM, and 91.3 µM, respectively, and the inhibitory effect of rosmarinic acid on OAT3 transport activity caused an in vivo pharmacokinetic interaction with furosemide by inhibiting its renal excretion and by increasing its plasma concentration. In conclusion, OAT1 and OAT3 are the major transporters that may regulate the pharmacokinetic properties of rosmarinic acid and may cause herb-drug interactions with rosmarinic acid, although their clinical relevance awaits further evaluation.

Enhanced Intestinal Absorption and Pharmacokinetic Modulation of Berberine and Its Metabolites through the Inhibition of P-Glycoprotein and Intestinal Metabolism in Rats Using a Berberine Mixed Micelle Formulation.

We aimed to develop a berberine formulation to enhance the intestinal absorption and plasma concentrations of berberine through the inhibition of P-glycoprotein (P-gp)-mediated efflux and the intestinal metabolism of berberine in rats. We used pluronic P85 (P85) and tween 80, which have the potential to inhibit P-gp and cytochrome P450s (i.e., CYP1A2, 2C9, 2C19, 2D6, and 3A4). A berberine-loaded mixed micelle formulation with ratios of berberine: P85: tween 80 of 1:5:0.5 (w/w/w) was developed. This berberine mixed micelle formulation had a mean size of 12 nm and increased the cellular accumulation of digoxin via P-gp inhibition. It also inhibited berberine metabolism in rat intestinal microsomes, without significant cytotoxicity, up to a berberine concentration of 100 µM. Next, we compared the pharmacokinetics of berberine and its major metabolites in rat plasma following the oral administration of the berberine formulation (50 mg/kg) in rats with the oral administration of berberine alone (50 mg/kg). The plasma exposure of berberine was significantly greater in rats administered the berberine formulation compared to rats administered only berberine, which could be attributed to the increased berberine absorption by inhibiting the P-gp-mediated berberine efflux and intestinal berberine metabolism by berberine formulation. In conclusion, we successfully prepared berberine mixed micelle formulation using P85 and tween 80 that has inhibitory potential for P-gp and CYPs (CYP2C19, 2D6, and 3A4) and increased the berberine plasma exposure. Therefore, a mixed micelle formulation strategy with P85 and tween 80 for drugs with high intestinal first-pass effects could be applied to increase the oral absorption and plasma concentrations of the drugs.

Quasi-Solid-State Electrolyte Synthesized Using a Thiol-Ene Click Chemistry for Rechargeable Lithium Metal Batteries with Enhanced Safety.

Liquid electrolytes currently used in lithium-ion batteries have critical drawbacks such as high flammability, high reactivity toward electrode materials, and solvent leakage. To overcome these issues, most recent research has focused on synthesis and characterization of highly conductive gel-type polymer electrolytes containing large numbers of organic solvents in the polymer matrix. There are still many hurdles to overcome, however, before they can be applied to commercial-level lithium-ion batteries. Since a large amount of organic solvent is required to achieve high ionic conductivity, battery safety is not significantly enhanced. In our study, we synthesized highly conductive quasi-solid-state electrolytes (QSEs) containing an ionically conductive oligomer (polycaprolactone triacrylate) and a small amount of organic solvent by employing click chemistry. In the QSE, polycaprolactone participates in dissociation of lithium salt and migration of lithium ions, resulting in high ionic conductivity. The Li/LiNi0.6Co0.2Mn0.2O2 cell that used this QSE exhibited good cycling performance and enhanced thermal stability, and durability; no organic solvent leakage was observed even under high pressure.