Crystal Structure, Solubility, and Pharmacokinetic Study on a Hesperetin Cocrystal with Piperine as Coformer

Hesperetin (HES) is a key biological active ingredient in citrus peels, and is one of the natural flavonoids that attract the attention of researchers due to its numerous therapeutic bioactivities that have been identified in vitro. As a bioenhancer, piperine (PIP) can effectively improve the absorption of insoluble drugs in vivo. In the present study, a cocrystal of HES and PIP was successfully obtained through solution crystallization. The single-crystal structure was illustrated and comprehensive characterization of the cocrystal was conducted. The cocrystal was formed by two drug molecules at a molar ratio of 1:1, which contained O–H–O hydrogen bonds between the carbonyl and ether oxygen of PIP and the phenolic hydroxyl group of HES. In addition, a solubility experiment was performed on powder cocrystal in simulated gastrointestinal fluid, and the result revealed that the cocrystal improves the dissolution behavior of HES compared with that of the pure substance. Furthermore, HES’s bioavailability in the cocrystal was six times higher than that of pristine drugs. These results may provide an efficient oral formulation for HES.

The physics of Empty Liquids: from Patchy particles to Water

Empty liquids represent a wide class of materials whose constituents arrange in a random network through reversible bonds. Many key insights on the physical properties of empty liquids have originated almost independently from the study of colloidal patchy particles on one side, and a large body of theoretical and experimental research on water on the other side. Patchy particles represent a family of coarse-grained potentials that allows for a precise control of both the geometric and the energetic aspects of bonding, while water has arguably the most complex phase diagram of any pure substance, and a puzzling amorphous phase behavior. It was only recently that the exchange of ideas from both fields has made it possible to solve long-standing problems and shed new light on the behavior of empty liquids. Here we highlight the connections between patchy particles and water, focusing on the modelling principles that make an empty liquid behave like water, including the factors that control the appearance of thermodynamic and dynamic anomalies, the possibility of liquid-liquid phase transitions, and the crystallization of open crystalline structures.

To be liberated the Vaisheshika way, or the Vaisheshika attempt at a «Negative Soteriology» by the Indian school of philosophy

The article examines the original concept of the Vaisheshika school, criticized by other Indian philosophers, according to which Self (Atman), freed from the bonds of rebirth (saṃsāra), is a pure substance (dravya), devoid of consciousness, which is believed to be its impermanent quality (guna); the opponents compared the Vaisheshika's liberated Self with a stone or a log. The author proposes an explanation of the Vaisheshika liberation doctrine (soteriology) within the framework of its categoriology, in which consciousness and Atman belong to different categories, respectively, guna and dravya. Vaisheshika proclaims knowledge of the six categories to be the highest spiritual goal (nihshreyasa), which, in turn, comes from the pure Dharma (Merit). The reason why the Vaisheshikas felt obliged to add a pure Dharma as the final step towards liberation (which distinguishes Vaisheshika from other schools, emphasizing the soteriological value of knowledge) is explained by assuming the Dharma's capacity to overcome a dichotomy of merit-demerit (dharma-adharma) as the main factor responsible for the rebirth of an embodied ātman. The pure Dharma, due to all the positive karmic energy accumulated during countless reincarnations of the soul, arises at the very last moment in a person's life to purufy his/her true Atman from the law of karma and rebirth. Since nothing can be said about Atman's future, it is not a "liberation for", but a "liberation from", which can be called a "negative soteriology".

Elimination of Interionic Hydrogen Bonding in The Imidazolium-Based Ionic Liquids

Hydrogen bonding is a phenomenon of paramount importance in room-temperature ionic liquids. The presence or absence of the hydrogen bond drastically alternates self-diffusion, shear viscosity, phase transition points, and other key properties of a pure substance. For certain applications, the presence of cation-anion hydrogen bonding is undesirable. In the present paper, we investigate perspectives of removing the hydrogen...fluorine interionic attraction in the imidazolium borates, the strongest non-covalent interaction in this type of system. Chemical modification of the tetrafluoroborate anion not only eliminates hydrogen bonding but also changes the most thermodynamically preferable orientation of the cation in the vicinity of the anion. Although the most acidic hydrogen atom of the imidazole ring remains the paramount electrophilic center of the cation, it does not engender a strong electrostatically driven coordination pattern with the properly modified anions. The reported new physical insights help compose more robust ionic liquids and tune solvation properties of the imidazolium-based RTILs.

Assessment and investigation of measurement uncertainty of standard samples of substances and materials in physicochemical measurements based on standard test methods

The article assessed and investigated the uncertainty of measurements of standard samples of substances and materials in physicochemical measurements based on standard test methods. A general approach to estimating the sources of uncertainty of standard samples is described. Uncertainties from heterogeneity of standard sample material. uncertainty from instability of standard sample characteristic values. uncertainty from method of setting reference value are investigated. Purity of substances is the main parameter that needs to be paid attention to when studying their properties. This is all the more important when it comes to using a pure substance as some approximation to the prototype reference value. since only this unit of seven main units in the International System of Units (SI system) does not have its own standard. In this sense. an important scientific task is the comprehensive study of pure substances for their practical use as benchmarks for comparison in metrological works and analytical research. The main and very important part of the measurement traceability system are materials with certified (certified) content of components and defined uncertainties of these values (standard samples of the approved type). which require pure substances certified at a higher - reference level. i.e. comparison standards.

Solid-State Stability Profiling of Ramipril to Optimize Its Quality Efficiency and Safety

High global expenditure on out-of-label-date drugs, along with safety concerns associated with the accumulation of degradation impurities, justify the need for stability profiling. In this article, a comprehensive study on the solid-state stability of ramipril (RAM) was performed via isothermal methods under stress conditions. A validated stability-indicating HPLC protocol was used. The effects of various factors on the rate of RAM degradation were investigated, including: temperature, relative air humidity (RH), excipients (talc, starch, methylcellulose and hydroxypropyl methylcellulose), mode of tablet storage, and immediate packaging. The degradation impurities were also identified by HPLC–MS. It was found that RAM was unstable, and temperature accelerated its degradation. RAM was also vulnerable to RH changes, suggesting that it must be protected from moisture. The reaction followed first-order kinetics. The studied excipients stabilized RAM as a pure substance. The tableting process deteriorated its stability, explaining the need for appropriate immediate packaging. RAM in the form of tablets must be stored in blisters, and it cannot be crushed into two halves. The degradation impurities were ramiprilat and the diketopiperazine derivative.

Effects of single and 7-fold administration of a complex of albendazole with disodium salt of glycyrrhizic acid to hamsters infected with Opisthorchis felineus

The purpose of the research is to evaluate the effect of albendazole as part of the supramolecular complex with disodium salt of glycyrrhizic acid obtained by solid-phase mechanical treatment.Materials and methods. The anthelmintic activity of the complex and its effect on the host organism was assessed on hamsters infected with Opisthorchis felineus by single and 7-fold administration at 45 days after infection. After 21 days, we counted the number of helminthes in the liver, and conducted a morphometric analysis of the liver and spleen, and detected biochemically the activity of alanine aminotransferase and aspartate aminotransferase in the animals’ blood serum.Results and discussion. The number of O. felineus significantly decreased after 7-fold, but not a single, administration of albendazole (ABZ) and ABZ-Na2GA complex (1 : 10). The administrated substances had no effect on the weight gain of the animals and the daily consumption of the pellets. At the same time, ABZ only as part of the complex normalized the weight of the liver and spleen in hamsters infected with O. felineus and reduced the alanine aminotransferase activity. Consequently, a longer administration of ABZ as part of the complex with disodium glycyrrhizinate has not only a pronounced anthelmintic effect, but also improves some of the physiological parameters of hamsters to a greater extent than a pure substance.

Theoretical Analysis of Anticancer Cellular Effects of Glycoside Amides

Background: This article is a continuation of Theoretical Analysis for the Safe Form and Dosage of Amygdalin Product and Theoretical Study of the Process of Passage of Glycoside Amides through the Cell Membrane of Cancer Cell. They consider some possible natural modifications and hypothesize that it is not nitrile glycosides that have antitumor properties, but their amide / carboxyl derivatives. The possibility of using this circumstance in conservative oncology is also considered. A mechanism for crossing the cell membrane and overcoming the immune functions of the cancer cell is presented. The physiologically active cancer cell itself is quite inert to external influences. It is far more stable than any physiologically active structural and/or functional organismal cell. Its defenses are discussed in detail in the article, and its main weakness was defined, namely: the cancer cell feeds mainly on carbohydrates and/ or carbohydrate complexes. In an effort to preserve its gene set, it has evolved to counteract biologically active substances by maximally preventing its passage through its cell membrane. It is this property that could be used to minimize its effect on the whole body. In the same article, based on theoretical calculations and literature references, a hypothesis is stated: cancers could turn from severe infectious to controlled chronic ones (similar to diabetes, chronic hepatitis, etc.) Objective: The pharmaceutical form allows deviation from the chemically pure substance. It is a convenient and at the same time accessible (from a financial and/or technological point of view) form for admission by patients. Due to the great variety of natural glycosamide nitriles (starting material for the production of amide/ carboxylic acid), modern pharmacology allows their combined intake by chemical nature and concentration of the active form crossing the cell membrane. Natural nitrile glycosides hydrolyzed to amide/carboxylic acid are still unexplored, but with great theoretical potential. As biologically active substances, these compounds also have significant toxicity. One of the purposes of this article is to organize laboratory tests on animals. Methods: A comparative analysis is performed on the basis of stoichiometric calculations for the concentration of the active form and the prediction of the bioactivity. For this purpose, the following methodology is applied: Data analysis for active anticancer cell molecular form and Determination of the drug dose. The derived chemicals obtained immediately after the passage of glycosamide across the cancer cell membrane are: (R)-2-hydroxy-2-phenylacetamide, (R)-2-hydroxy-2-(4-hydroxyphenyl)acetamide, (R)-2-hydroxy-2-(3-hydroxyphenyl)acetamide, 2-hydroxy-2-methylpropanamide, (S)-2-hydroxy-2-methylbutanamide, 2-hydroxy-3-methylbut-2-enamide, (2Z,4E)-4-(2-amino-1-hydroxy-2-oxoethylidene)hex-2-enedioic acid, (S)-1-hydroxycyclopent-2-ene-1-carboxamide, (1S,4S)-1,4-dihydroxycyclopent-2-ene-1-carboxamide, (1R,4R)-1,4,5-trihydroxycyclopent-2-ene-1-carboxamide, (Z)-2-((4S,6R)-4,6-dihydroxycyclohex-2-en-1-ylidene)acetamide, (R)-2-hydroxy-3-methylbutanamide, (E)-2-((4S,5R,6R)-4,5,6-trihydroxycyclohex-2-en-1-ylidene)acetamide, (Z)-2-((4R,5R,6S)-5,6-dihydroxy-4-methoxycyclohex-2-en-1-ylidene)acetamide, (E)-2-((4R,6S)-4,6-dihydroxycyclohex-2-en-1-ylidene)acetamide и (E)-2-((4S,5R,6R)-4,5,6-trihydroxycyclohex-2-en-1-ylidene)acetamide. Results: The use of two or more pharmaceutical forms would not prevent their penetration subject to the mass ratios between the active antitumor amide and the active carboxyl transfer form. Conclusion: Amides resulting from the hydrolysis of nitrile glycosides would have the ability to cross the cell membrane of a cancer cell and thus cause its cellular response. The pharmaceutical form must represent the exact amide / carboxylic acid ratio for the corresponding active anticancer cell form.

Phase-field simulations of isomorphous binary alloys subject to isothermal and directional solidification

PurposeIn this work, with a goal to ultimately forward the advancement of additive manufacturing research, the author applies the Wheeler-Boettinger-McFadden model through a progressive series of increasingly complex solidification problems illustrating the evolution of both dendritic as well as columnar growth morphologies. For purposes of convenience, the author assumes idyllic solutions (i.e. the excess energies associated with mixing solid and liquid phases can be neglected).Design/methodology/approachIn this work, the author applied the phase-field model through a progressive series of increasingly complex solidification problems, illustrating the evolution of both dendritic as well as columnar growth morphologies. Beginning with a non-isothermal treatment of pure Ni, the author further examined the isothermal and directional solidification of Cu–Ni binary alloys.Findings(1) Consistent with previous simulation results, solidification simulations from each of the three cases revealed the presence of parabolic, dendrite tips evolving along directions of maximum interface energy. (2) For pure Ni simulations, changes in the anisotropy and noise magnitudes resulted in an increase of secondary dendritic branches and changes in the direction of propagation. The overall shape of the primary structure tended also to elongate with increased anisotropy. (3) For simulations of isothermal solidification of Ni–Cu binary alloys, the development of primary and secondary dendrite arm formation followed similar patterns associated with a pure substance. Calculations of dendrite tip velocity tended to increase monotonically with increasing anisotropy in accordance with previous research. (4) Simulations of directional solidification of Ni–Cu binary alloys with a linear temperature profile demonstrated the presence of cellular dendrites with relatively weak side-branching. The occurrence of solute trapping was also apparent between the primary dendrite columns. Dendrite tip velocities increased with increasing cooling rate.Originality/valueThis research, particularly the section devoted to directional solidification of binary alloys, describes a novel numerical framework and platform for the parametric analysis of various microstructural related quantities, including the effects due to changes in temperature gradient and cooling rate. Both the evolution of the phase and concentration are resolved.