Improving dissolution kinetics of pharmaceuticals by fluidized bed impregnation of active pharmaceutical ingredients

Investigational drugs are increasingly becoming less soluble in aqueous media, thus, presenting real challenges during development. Previous work has successfully demonstrated the manufacturing of pharmaceuticals using fluidized bed (FB) impregnation of APIs onto porous carriers. This study demonstrates the usefulness of FB impregnation in formulating poorly soluble drugs. We show that dissolution of Fenofibrate is greatly improved by FB impregnation onto Neusilin^® (Fuji Health Science Inc, Burlington, NJ USA), a synthetic amorphous form of magnesium alumino‐metasilicate. We impregnate Neusilin^® for range of loadings and examine Fenofibrate's physical state. Dissolution of impregnated formulations is drug loading dependent and loadings below 40% show great improvement (decrease) in release time compared to physical blend. Release times are further improved by milling. We also examine feasibility of coimpregnating Fenofibrate with additives and observe stability (1.5 years) of the amorphous form of Fenofibrate inside Neusilin^®. This stabilization significantly improves Fenofibrate's dissolution kinetics, making our formulation comparable to one of the current market formulations, TriCor^® tablets (AbbVie Inc, North Chicago, IL USA). © 2016 American Institute of Chemical Engineers AIChE J, 62: 4201–4214, 2016     

Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs

A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non‐aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane‐ and cubane‐containing analogues were found to possess higher themodynamic solubility, whereas cubane‐ and cyclohexyl‐containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP‐B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off‐target effects.     

Evaluation of mass loss of weld-deposited hardfacing with cored wire Ti-FeCrC alloy

In this article, we have studied the mass loss of hardfacing applied by flux-cored arc welding. Heat input, shielding gas and number of layers of coating were changed to application of Fe–Cr–Ti–C self-shielded tubular wire. Overlapping beads were deposited on plates of carbon steel AISI 1020 to analyse the mass loss, hardness and microstructure. For the analysis of mass loss, beads were deposited forming overlapping layers of coatings. Hardness measurements were performed on the surface of the specimens of wear. A rubber wheel abrasion tester was used to access the mass loss of coatings. The coatings had retained austenite and martensite microstructure with carbides finely dispersed in the matrix. The main factors that contributed to the increase in mass loss were the cracks due to higher cooling rate of the samples deposited with low heat input, the dilution in the first layer of all samples also contributed to the increase in mass loss. The smallest mass losses were those deposited coatings with high heat input, the second and fourth layers, the samples AC2, AC4 and AS2. The volume fraction of titanium carbides contributed to the decrease in the mean free path between the particles of carbides and increased the wear resistance of the coatings.     

Study of the Effects of LAS and Zein Concentrations on Protein Solubilization

The effects of both linear alkylbenzene sulfonate (LAS) and zein protein concentrations on protein solubilization were investigated to better understand the influence of increasing concentration of the surfactant on protein denaturation and skin irritation. Different methods have been used for the determination of the amount of protein dissolved. A wide range of LAS concentrations and zein amounts were used. The results confirm that protein solubilization increases with LAS concentration increase and demonstrate that a minimum LAS/Zein ratio exists for all the zein to be dissolved.     

Kinetic study of liquid lipase-catalyzed glycerolysis of olive oil using Lipozyme TL 100L

Monoacylglycerol (MAG) and diacylglycerol (DAG) are two natural components found in most edible oils and fats. Conventional synthesis of MAG and DAG is usually conducted by glycerolysis of triacylglycerol (TAG) at high temperatures (above 200°C) in the presence of an alkaline catalyst. In this work, the synthesis of MAG and DAG using enzymatic glycerolysis of olive oil was investigated using Tween 80 as surfactant, n-butanol as co-surfactant and the novel lipase in free/liquid formulation Lipozyme TL 100L as catalyst. Experimental design was used to evaluate the effect of enzyme load and reaction temperature on the feedstock conversion. Enzyme load and system temperature were significant variables in the statistical design and the best condition was found at 35°C, 7.5 vol% of Lipozyme TL 100L and glycerol to oil volumetric ratio of 2:1 with conversion of TAG at approximately 98% after 2 h of process. A mathematical model based on the Ping-Pong Bi-Bi mechanism was used to describe the reaction kinetics. The model adequately described the behavior of the system and can be a useful tool for the design of reactors in larger scales.     

Thermal and flammability properties influenced by Zn/Al,Co/Al,and Ni/Al layered double hydroxide in low-density polyethylene nanocomposites

Layered double hydroxide (LDH) containing different metal constituents (Zn, Co, and Ni) was intercalated with different organic anions and has been used as fillers in low-density polyethylene (LDPE), and its thermal and flammability behavior was evaluated. The best thermal stability (∆T_0.5 = 21 °C) was obtained with the LDPE-Ni/Al-dodecyl sulfate (4 wt %) nanocomposite. Addition of hydrophobic LDHs systematically decreases the enthalpy of melting and crystallization compared to the neat polymer. In LDPE-Co/Al-dodecyl sulfate (2 wt %) nanocomposite, the melting and crystallization enthalpies declined by about 45 J/g, indicating a good interaction of the filler with the polymer matrix. A reduction of 20% of the flammability for the LDPE-Ni/Al-stearate (4 wt %) nanocomposite was obtained. On the other hand, Zn–Co LDH as filler in LDPE nanocomposite did not affect effectively the same property. In an innovative study, results indicate that different metal constituents and interlayer anion of LDH as filler can change thermal and flammability properties of the polymer nanocomposite. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48737.     

Total Electron Detachment and Induced Cationic Fragmentation Cross Sections for Superoxide Anion (O2−) Collisions with Benzene (C6H6) Molecules

In this study, novel experimental total electron detachment cross sections for O₂⁻ collisions with benzene molecules are reported for the impact energy range (10–1000 eV), as measured with a transmission beam apparatus. By analysing the positively charged species produced during the collision events, relative total ionisation cross sections were derived in the incident energy range of 160–900 eV. Relative partial ionisation cross sections for fragments with m/z ≤ 78 u were also given in this energy range. We also confirmed that heavier compounds (m/z > 78 u) formed for impact energies between 550 and 800 eV. In order to further our knowledge about the collision dynamics governing the fragmentation of such heavier molecular compounds, we performed molecular dynamics calculations within the framework of the Density Functional Theory (DFT). These results demonstrated that the fragmentation of these heavier compounds strongly supports the experimental evidence of m/z = 39–42, 50, 60 (u) cations formation, which contributed to the broad local maximum in the total ionisation observed from 550 to 800 eV. This work reveals the reactivity induced by molecular anions colliding with hydrocarbons at high energies, processes that can take place in the interstellar medium under various local conditions.     

Leptosphaeria maculans-Brassica napus Battle: A Comparison of Incompatible vs. Compatible Interactions Using Dual RNASeq

Leptosphaeria maculans causes blackleg disease, which is one of the most destructive diseases of canola (Brassica napus L.). Due to the erosion of the current resistance in B. napus, it is pivotal to introduce new resistant genotypes to the growers. This study evaluated the potential of Rlm7 gene as resistance to its corresponding avirulence AvrLm7 gene is abundant. The Rlm7 line was inoculated with L. maculans isolate with AvrLm7; UMAvr7; and the CRISPR/Cas9 knockout AvrLm7 mutant, umavr7, of the same isolate to cause incompatible and compatible interactions, respectively. Dual RNA-seq showed differential gene expressions in both interactions. High expressions of virulence-related pathogen genes-CAZymes, merops, and effector proteins after 7-dpi in compatible interactions but not in incompatible interaction—confirmed that the pathogen was actively virulent only in compatible interactions. Salicyclic and jasmonic acid biosynthesis and signaling-related genes, defense-related PR1 gene (GSBRNA2T00150001001), and GSBRNA2T00068522001 in the NLR gene family were upregulated starting as early as 1- and 3-dpi in the incompatible interaction and the high upregulation of those genes after 7-dpi in compatible interactions confirmed the early recognition of the pathogen by the host and control it by early activation of host defense mechanisms in the incompatible interaction.     

Bioactive compounds present in the Mediterranean sofrito

Sofrito is a key component of the Mediterranean diet, a diet that is strongly associated with a reduced risk of cardiovascular events. In this study, different Mediterranean sofritos were analysed for their content of polyphenols and carotenoids after a suitable work-up extraction procedure using liquid chromatography/electrospray ionisation-linear ion trap quadrupole-Orbitrap-mass spectrometry (LC/ESI-LTQ-Orbitrap-MS) and liquid chromatography/electrospray ionisation tandem triple quadrupole mass spectrometry (LC/ESI-MS-MS). In this way, 40 polyphenols (simple phenolic and hydroxycinnamoylquinic acids, and flavone, flavonol and dihydrochalcone derivatives) were identified with very good mass accuracy (<2 mDa), and confirmed by accurate mass measurements in MS and MS² modes. The high-resolution MS analyses revealed the presence of polyphenols never previously reported in Mediterranean sofrito. The quantification levels of phenolic and carotenoid compounds led to the distinction of features among different Mediterranean sofritos according to the type of vegetables (garlic and onions) or olive oil added for their production.