PEG-based solid dispersions enhanced the solubility and dissolution of eprosartan mesylate in-vitro

Abstract - This study investigates the effect of solid dispersions prepared from of polyethylene glycol (PEG) 3350 and 6000 Da alone or combined with the non-ionic surfactant Tween 80 on the solubility and dissolution rate of a poorly soluble drug eprosartan mesylate (ESM) in attempt to improve its bioavailability following its oral administration.

INTRODUCTION

ESM is a potent anti-hypertension [1]. It has low water solubility and is classified as a Class II drug as per the Biopharmaceutical Classification Systems (BCS) leading to low and variable oral bioavailability (approximately 13%). [2]. Thus, improving ESM solubility and/or dissolution rate would eventually improve the drug bioavailability. Solid dispersion is widely used technique to improve the water solubility of poorly water-soluble drugs employing various biocompatible polymers. In this study, we aimed to enhance the solubility and dissolution of EMS employing solid dispersion (SD) formulated from two grades of poly ethylene glycol (PEG) polymers (i.e. PEG 3350 & PEG 6000 Da) either individually or in combination with Tween 80.

MATERIALS AND METHODS

ESM SDs were prepared by solvent evaporation method using either PEG 3350 or PEG 6000 at various (drug: polymer, w/w) ratios 1:1, 1:2, 1:3, 1:4, 1:5 alone or combined with Tween 80 added at fixed percentage of 0.1 of drug by weight?. Physical mixtures (PMs) of drug and carriers were also prepared at same ratios. Drug solid dispersions and physical mixtures were characterized in terms of drug content, drug dissolution using dissolution apparatus USP II and assayed using HPLC method. Drug dissolution enhancement ratio (ER %) from SD in comparison to the plain drug was calculated. Drug-polymer interactions were evaluated using Differential Scanning Calorimetry (DSC) and FT-IR.

RESULTS AND DISCUSSION

The in vitro solubility and dissolution studies showed SDs prepared using both polymers produced a remarkable improvement (p<0.05) in comparison to the plain drug which reached around 32% (Fig. 1). The dissolution enhancement ratio was polymer type and concentration-dependent. Adding Tween 80 to the SD did not show further dissolution enhancement but reduced the required amount of the polymer to get the same dissolution enhancement. The DSC and FT-IR studies indicated that using SD resulted in transformation of drug from crystalline to amorphous form.

CONCLUSIONS

This study indicated that SDs prepared by using both polymers i.e. PEG 3350 and PEG 6000 improved the in-vitro solubility and dissolution of ESM remarkably which may result in improving the drug bioavailability in vivo.

Acknowledgments

This work is a part of MSc thesis of O.M. Ali at the Faculty of Pharmacy, Aleppo University, Syria.

REFERENCES

[1] Ruilope L, Jager B: Eprosartan for the treatment of hypertension. Expert Opin Pharmacother 2003; 4(1):107-14

[2] Tenero D, Martin D, Wilson B, Jushchyshyn J, Boike S, Lundberg, D, et al. Pharmacokinetics of intravenously and orally administered Eprosartan in healthy males: absolute bioavailability and effect of food. Biopharm Drug Dispos 1998; 19(6): 351- 6.

The use of binary polymeric networks in stabilising polyethylene oxide solid dispersions

The objective of this study was to determine if a high Tg polymer (Eudragit® S100) could be used to stabilize amorphous domains of polyethylene oxide (PEO) and hence improve the stability of binary polymer systems containing celecoxib (CX). We propose a novel method of stabilizing the amorphous PEO solid dispersion through inclusion of a miscible, high Tg polymer, namely, that can form strong inter-polymer interactions. The effects of inter-polymer interactions and miscibility between PEO and Eudragit S100 are considered. Polymer blends were first manufactured via hot-melt extrusion at different PEO/S100 ratios (70/30, 50/50, and 30/70 wt/wt). Differential scanning calorimetry and dynamic mechanical thermal analysis data suggested a good miscibility between PEO and S100 polymer blends, particularly at the 50/50 ratio. To further evaluate the system, CX/PEO/S100 ternary mixtures were extruded. Immediately after hot-melt extrusion, a single Tg that increased with increasing S100 content (anti-plasticization) was observed in all ternary systems. The absence of powder X-ray diffractometry crystalline Bragg’s peaks also suggested amorphization of CX. Upon storage (40°C/75% relative humidity), the formulation containing PEO/S100 at a ratio of 50:50 was shown to be most stable. Fourier transform infrared studies confirmed the presence of hydrogen bonding between Eudragit S100 and PEO suggesting this was the principle reason for stabilization of the amorphous CX/PEO solid dispersion system.

Magnetic Flux Cancellation in Ellerman Bombs

Ellerman Bombs (EBs) are often found to be co-spatial with bipolar photospheric magnetic fields. We use Hα imaging spectroscopy along with Fe i 6302.5 Å spectropolarimetry from the Swedish 1 m Solar Telescope (SST), combined with data from the Solar Dynamic Observatory, to study EBs and the evolution of the local magnetic fields at EB locations. EBs are found via an EB detection and tracking algorithm. Using NICOLE inversions of the spectropolarimetric data, we find that, on average, (3.43 ± 0.49) × 1024 erg of stored magnetic energy disappears from the bipolar region during EB burning. The inversions also show flux cancellation rates of 1014–1015 Mx s‑1 and temperature enhancements of 200 K at the detection footpoints. We investigate the near-simultaneous flaring of EBs due to co-temporal flux emergence from a sunspot, which shows a decrease in transverse velocity when interacting with an existing, stationary area of opposite polarity magnetic flux, resulting in the formation of the EBs. We also show that these EBs can be fueled further by additional, faster moving, negative magnetic flux regions.

Development of the Oxide Ion Conductor Na0.5Bi0.5TiO3 (NBT) for Solid Oxide Cells

Na0.5Bi0.5TiO3 (NBT) is a well-known lead-free piezoelectric material with potential to replace lead zirconate titanate (PZT),1 however high leakage conductivity for the material has been widely reported.2 Through a combination of Impedance Spectroscopy (IS), O2- ion transference (EMF) number experiments and O18 tracer diffusion measurements, combined with Time-of-flight Secondary Ion Mass Spectrometry (TOFSIMS), it was identified that this leakage conductivity was due to oxygen ion conductivity. The volatilization of bismuth during synthesis, causing oxygen vacancies, is believed to be responsible for the leakage conductivity.3 The oxide-ion conductivity, when doped with magnesium, exceeds that of yttria-stabilized zirconia (YSZ) at ~500 °C,3 making it a potential electrolyte material for Intermediate Temperature Solid Oxide Cells (ITSOCs). Figure 1 shows the comparison of bulk oxide ion conductivity between 2 at.% Mg-doped NBT and other known oxide ion conductors.

As part of the UK wide £5.7m 4CU project, research has concentrated on trying to develop NBT for use in Intermediate Temperature Solid Oxide Cells (ITSOCS). With the aim of achieving mixed ionic and electronic conduction, transition metals were chemically doped on to the Ti-site. A range of experimental techniques was used to characterize the materials aimed at investigating both conductivity and material structure (Scanning Electron Microscopy (SEM), IS, X-ray Photoelectron Spectroscopy (XPS) and X-ray Absorption Spectroscopy (XAS)). The potential for NBT as an ITSOC material, as well as the challenges of developing the material, will be discussed.

(1) Takenaka T. et al. Jpn. J. Appl. Phys 1999, 30, 2236.

(2) Hiruma Y. et al. J. Appl. Phys 2009, 105, 084112.

(3) Li. M. et al. Nature Materials 2013, 13, 31.

Flash-Sintering and Characterization of La0.8Sr0.2Ga0.8Mg0.2O3-δ Electrolytes for Solid Oxide Fuel Cells

La_0.8Sr_0.2Ga_0.8Mg_0.2O_3-δ (LSGM), a promising electrolyte material for intermediate temperature solid oxide fuel cells, can be sintered to a fully dense state by a flash-sintering technique. In this work, LSGM is sintered by the current-limiting flash-sintering process at 690°C under an electric field of 100 V cm^-1, in comparison with up to 1400°C or even higher temperature in conventional furnace sintering. The resultant LSGM samples are investigated by scanning electron microscopy, X-ray diffraction, and electrochemical impedance spectroscopy. The SEM images exhibit well-densified microstructures while XRD results show that the perovskite structure after flash-sintering does not changed. EIS results show that the conductivity of LSGM sintered by the current-limiting flash-sintering process increases with sintering current density value. The conductivity of samples sintered at 120 mA mm^-2 reaches 0.049 σ cm^-1 at 800°C, which is approximate to the value of conventional sintered LSGM samples at 1400°C. Additionally, the flash-sintering process is interpreted by Joule heating theory. Therefore, the current-limiting flash-sintering technique is proved to be an energy-efficient and eligible approach for the densification of LSGM and other materials requiring high sintering temperature.

High performance cobalt-free Cu1.4Mn1.6O4 spinel oxide as an intermediate temperature solid oxide fuel cell cathode

In this work Cu_1.4Mn_1.6O₄ (CMO) spinel oxide is prepared and evaluated as a novel cobalt-free cathode for intermediate temperature solid oxide fuel cells (IT-SOFCs). Single phase CMO powder with cubic structure is identified using XRD. XPS results confirm that mixed Cu⁺/Cu²⁺ and Mn³⁺/Mn⁴⁺ couples exist in the CMO sample, and a maximum conductivity of 78 S cm⁻¹ is achieved at 800 °C. Meanwhile, CMO oxide shows good thermal and chemical compatibility with a 10 mol% Sc₂O₃ stabilized ZrO₂ (ScSZ) electrolyte material. Impedance spectroscopy measurements reveals that CMO exhibits a low polarization resistance of 0.143 Ω cm² at 800 °C. Furthermore, a Ni-ScSZ/ScSZ/CMO single cell demonstrates a maximum power density of 1076 mW cm⁻² at 800 °C under H₂ (3% H₂O) as the fuel and ambient air as the oxidant. These results indicate that Cu_1.4Mn_1.6O₄ is a superior and promising cathode material for IT-SOFCs.

Fabrication and characterization of SSZ tape cast electrolyte-supported solid oxide fuel cells

A 10 mol%Sc₂O₃, 1 mol%CeO₂ stabilized-ZrO₂ (SSZ) powder was successfully prepared using the sol-gel method. Subsequent SSZ electrolyte pellets were prepared by tape casting technique and sintered at 1400 °C, 1450 °C, 1500 °C, 1550 °C and 1600 °C. These were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM) and electrochemical impedance spectroscopy (EIS). SSZ showed a pure cubic phase after sintering, the grain size of SSZ increased with the increase of sintering temperature. The SSZ sintered at 1550 °C showed the highest ion conductivity. The maximum power densities of Ni-SSZ/SSZ/La_0.8Sr_0.2MnO_3-δ (LSM)-SSZ single cells sintered at 1550 °C were 0.18, 0.36, 0.51 and 0.72 W cm^-2 at 650, 700, 750 and 800 °C, respectively. The polarization resistance (R_p) of the single cell attained 0.201 Ω cm² at 800 °C.

Detector for imaging and dosimetry of laser-driven epithermal neutrons by alpha conversion

An epithermal neutron imager based on detecting alpha particles created via boron neutron capture mechanism is discussed. The diagnostic mainly consists of a mm thick Boron Nitride (BN) sheet (as an alpha converter) in contact with a non-borated cellulose nitride film (LR115 type-II) detector. While the BN absorbs the neutrons in the thermal and epithermal ranges, the fast neutrons register insignificantly on the detector due to their low neutron capture and recoil cross-sections. The use of solid-state nuclear track detectors (SSNTD), unlike image plates, micro-channel plates and scintillators, provide safeguard from the x-rays, gamma-rays and electrons. The diagnostic was tested on a proof-of-principle basis, in front of a laser driven source of moderated neutrons, which suggests the potential of using this diagnostic (BN+SSNTD) for dosimetry and imaging applications.