Novel Methotrexate-Loaded Zein Nanoparticles With Improved and Extended Biopharmaceutical Performance: QbD-Steered Development, and Extensive In Vitro and In Vivo Evaluation

The current work entails QbD-enabled preparation of methotrexate-loaded nanoparticles (NPs) using zein as the release-controlling natural polymer. Initially, quality risk estimationand factor screening studies using Taguchi design were undertaken to delineate “vital few” process and material attributes among “plausible so many”. Further, formulation optimization using central composite design and validation using correlation plots and percent predictive bias was carried out. Optimized NPs exhibited mean size of 159 nm, zeta potential of 14.85 mV and entrapment of 50.23%. In vitro dissolution kinetic modelling unearthed non-Fickian drug release extension mechanism from the proposed zein NPs. In vitro MTT and apoptosis assay using MCF-7 cells and cellular uptake studies using Caco-2 cells indicate remarkably superior anticancer potential of zein NPs over pure methotrexate, ascribable to their nanometric size and cationic nature. In vivo pharmacokinetic studies in rat construed significant enhancement by 2.15-fold in AUC48h (p<0.001), 1.30-fold in Cmax (p<0.05), 3.67-fold in Tmax (p<0.001), and 1.38-fold in T1/2 (p<0.01), along with notably reduced variability in biopharmaceutical performance. Establishment of significant point-to-point level A in vitro/in vivo correlations (IVIVC) and kinetic modeling construed the robustness and prognostic ability of drug release studies. Robustness of the nanoformulation was ratified under refrigerated storage through six months’stability studies. Overall, the studies unequivocally indicate development of a stable nanoparticulate formulation with significantly enhanced extent, extension and consistency of biopharmaceutical performance, along with improved anticancer potential of methotrexate.

Mechanical Damage and Chemical Dissolution Kinetic Features of Limestone under Coupled Mechanical-Hydrological-Chemical Effects

To address the mechanical damages of limestone under the coupled mechanical(M)-hydrological(H)-chemical(C) effects, we performed uniaxial compression experiments and dissolution kinetics experiments on limestone in flowing and static solutions for different lengths of time. Through experiments, the peak strengths of the limestone under coupled MHC effects for different time lengths and the major ion concentrations in solutions were obtained. By analyzing the strength damage and chemical dissolution kinetic characteristics, we achieved the strength damage equations and chemical dissolution kinetic equations. Results show that when the solution shifted from the static state to the flowing state, and as its acidity increased, the peak strength loss of the limestone rose as well. The solution mobility had a more significant impact on the peak strength loss than the solution pH value. The limestone dissolution in flowing water was higher than in static water, indicating that solution mobility would promote the limestone dissolution. Among the contributing factors to limestone dissolution, the solution pH value showed the strongest impact, followed by the common-ion effect and then the salt effect. The research result is expected to provide a theoretical basis for maintaining the stability of rocks in geotechnical engineering practice and protection of stone cultural relics.

Study of Steel Electro-dissolution Behavior in Presence of Some Surfactants. Electrochemical Investigation and Surface Active Properties Determination

Steel electro-dissolution performance was investigated in orthophosphoric acid in the presence of N-oleyl 1.3 diaminopropane, Benzalkounuim chloride, Soduim lauryl sulphate and Di-Isononyl phthalate as a surfactant using potentiodynamic polarization measurements. The retardation performance of these surfactants was examined. The surfactant surface active parameters were estimated based on surface tension measurements. The parameters calculated comprise the critical micelle concentration (CMC), maximum surface excess (Гmax), minimum surface area (Amin) and effectiveness (πCMC). The micellization thermodynamic parameters (ΔGmic, ΔSmic) for the estimated surfactants were also computed. Results obtained from surface active properties are comparable with those gained from galvanostatic polarization measurements. Temperature influence on the steel dissolution performance was examined at 25 to 40oC range. Steel kinetic study in orthophosphoric acid- free solution and orthophosphoric acid containing surfactant was also examined. The dissolution kinetic and activated parameters were computed. Results based on microscopy measurement indicate that, addition of new four surfactants, resulting in the solution shows potential, a discrete progress in the metal texture was monitored. Improvement produced in electro-polishing bath by the investigated SAS that owing to the adsorption of such surface active agents on the anode surface.

Dissolution Kinetics of Chlorine from Iron Ore Sintering Dust

Chlorine is generated during iron ore sintering, mostly in the form of alkali chlorides and primarily accumulates in sintering dust, which must be removed before reusing. In this study, an in-situ monitor leaching system based was designed to detect chloride ion water leaching behaviors in real-time and improve the understanding of chlorine dissolution kinetic behaviors in water. Various parameters, including water leaching temperature, solid/liquid ratio, stirring speed, particle size and surfactant addition have been studied. Meanwhile their chlorine dissolution data exhibited a good fit to Stumm’s kinetic models. The results of kinetics analysis and transition state theory calculation on apparent activation energy demonstrated that the dissolution process was controlled by diffusion at low S/L ratio, while changed to be controlled by surface chemical reaction as the S/L ratio increased. Furthermore, increasing both temperature and stirring speed improved the chlorine removal speed. Moreover, reducing the particle size and adding 0.2% nonionic surfactant Triton X-100 reduced the surface energy and accelerated surface chemical reaction, which were also beneficial for removing chlorine from sintering dust. In addition, the SEM-EDS examination inferred that the existence of laurionite (PbOHCl) limited the chlorine dissolution rate to less than 97%, while beneficiation or hydrometallurgy treatment was needed to further remove chlorine.

A Dissolution Kinetic Study of Disperse Dye in Supercritical Carbon Dioxide to Design an Efficient Supercritical Dyeing Process

The dissolution behavior of dye in supercritical carbon dioxide influences the overall mass transfer that controls a supercritical dyeing process. Increasing the dissolution rate of the dye leads to shortening of the dyeing process time and can improve the efficiency of the process. Controlling the properties of the carbon dioxide flow is a good method to improve the dissolution rate of dyes. In this study, a dissolution kinetic model was designed by quantitatively analyzing and formulating the dissolution phenomenon of dyes using an in situ UV/Vis spectrometer. Through this model, the dissolution rate was compared by varying the geometric shape of the column containing the dye and the flow rate of carbon dioxide. Moreover, the correlation equation between the Reynolds number and Sherwood number was obtained through mass transfer coefficients derived under various conditions. In order to verify the utility of this equation, it was applied to a scaled-up device and the precise result could be predicted. This study can be useful in the design of dyeing processes and make-up equipment.

DISSOLUTION KINETIC OF MELOXICAM FROM HYDROPHILIC MATRIX-TYPE FILMS FOR TRANSDERMAL THERAPY

Taking into consideration the fact the transdermal administration of the active pharmaceutical ingredients can represent a therapeutic approach that increases the patient’s compliance, this study aims to evaluate the release of meloxicam (MX), a potent non-steroidal anti-inflammatory drug, incorporated in hydrophilic polymer-based matrices for transdermal therapeutic systems was studied. Three different formulations were realized by solvent casting method containing two types of hydroxypropyl methylcellulose (HPMCE5 with low viscosity and HPMC15000 with high viscosity) whose concentration was also varied. The drug release test was performed by Franz diffusion cell and the dissolution curves were analysed from a kinetical point of view by model dependent and model independent methods. Linearization by simple regression allowed the flux calculations of values that varied between 0.183 and 32.270 g/(cm2h). Based on the results obtained with the mathematical analysis, we can conclude that the MX release is influenced by the pH of the dissolution media and by the type and concentration of the matrix forming agent. Discrimination of model dependent mathematical models was done by the Akaike index with values between 49 and -62. The kinetic analysis of the MX releasing curves from the proposed formulations showed that Korsmeyer-Peppas was more suitable for the release characterisation of the active pharmaceutical ingredient from the transdermal therapeutic systems analysed.

Genesis Analysis of Large TiN Inclusion for High Strength Tire Cord Steel

In order to analyze the possible source of large TiN inclusion for the high strength tire cord steel. The remelting experiment was conducted via vacuum induction furnace in the laboratory and the artificially prepared TiN particles which of size 50-74 μm and 100-180 μm were added during the remelting process. Simultaneously, combined with the dissolution kinetic model of TiN particle to make a brief analysis for the genesis of lagre TiN inclusion detected in the wire rod. The results show that the TiN particle which of size 180 μm dissolved in the liquid steel completely at only a few seconds. The TiN inclusions detected in the remelted specimens are all of regular shape, which mainly formed during the solidification process, rather than the added TiN particle which are not completely dissolved. It is supposed that the large TiN inclusion detected in the wire rod most likely spring from the continuous casting mould fluxes.

Solubility analysis of venlafaxine hydrochloride polymorphs by shake-flask method and real time monitoring

Aims: The aqueous solubility of two polymorphic forms of venlafaxine hydrochloride was investigated. Methods: The pH-dependent solubility (SpH) over a wide pH range was measured by saturation shake-flask (SSF) method at 25 °C. The solubility of the free base form was depicted by the intrinsic solubility (So). To identify the solid form present at the solubility equilibrium, X-ray powder diffraction (XRPD) and Raman spectroscopy was carried out. The dissolution was studied using real time concentration monitoring applying fiber optic UV probes. Results: No difference was found in the SpH values of Form I and Form II, in the pH range 7.5-12. Solid phase isolated from pH 10-12 suspensions was identified as free base by XRPD and Raman spectroscopy. Precipitates separated from pH 7-8 samples were also identical product. The transition of polymorphs to the free base was supported by the real time dissolution analysis. Conclusion: In this study we demonstrated a good agreement of equilibrium solubility measured by SSF method and in-situ UV fiber optic method. µDISS ProfilerTM has the advantage to provide much more information about dissolution process; with this approach the dissolution kinetic, the supersaturation and the time needed to reach the equilibrium can be easily monitored.