Oral Dosage Development of a Human Rhinovirus and Non-Polio Enterovirus Inhibitor

Abstract

WIN 63843, a Picornavirus replication inhibitor, is physically and chemically stable in the solid state, to light, elevated temperature, and humidity. This 3-ary15-trifluoromethyl disubstituted 1,2,4-oxadiazole compound has very low water solubility but is highly soluble in ethanol and in safflower seed and corn oils. Solubility in the vegetable oils is doubled by the synergistic effect of ethanol at the 16% alcohol concentration. Vegetuble oil solutions of WIN 63843 are thermally stable but react slowly in the presence of light resulting in an amidoxime compound (WIN 65489) formed by opening of the 1,2,4-oxadiazole ring. This reaction does not occur in oil solutions containing small concentrations of ethanol. Of biophannaceutical interest, the addition of ethanol or PEG-400 solutions of WIN 63843 to human gastric fluid resulted in oily droplet formation whereas crystals form upon addition of these solutions to water. Also, the compound is greater than 8,000 times more soluble in human gastric fluid.     

Kinetic and Stability Study of an Investigative Antirhinovirus Compound

A hydrolytic acid and base catalyzed ring opening reaction has been demonstrated for a 1,2,4-oxadiazole antiviral compound (WIN 63843) resulting mainly in an amidoxime product. Decomposition products and related impurities were detected using a gradient HPLC method. The hydrolysis reaction was first-order for 35% ethanol/buffer solutions in a 50°C chamber or a light cabinet (1000 ft-candles), the greatest stability being between pH 4 and 6. Furthermore, increasing ethanol concentrations resulted in a great decrease in reaction rates. Therefore, for oral or aerosol solution formulations, light protection, pH control between 4 and 6 and the highest permissible ethanol concentrations would be advantageous. This study has shown that the highly electronegative trifluoromethyl group at the 5 position increases the lability of a 1,2,3-oxdiazole compound.     

Kinetic and Stability Study of an Investigative Antirhinovirus Compound

Abstract

A hydrolytic acid and base catalyzed ring opening reaction has been demonstrated for a 1,2,4-oxadiazole antiviral compound (WIN 63843) resulting mainly in an amidoxime product. Decomposition products and related impurities were detected using a gradient HPLC method. The hydrolysis reaction was first-order for 35% ethanol/buffer solutions in a 50°C chamber or a light cabinet (1000 ft-candles), the greatest stability being between pH 4 and 6. Furthermore, increasing ethanol concentrations resulted in a great decrease in reaction rates. Therefore, for oral or aerosol solution formulations, light protection, pH control between 4 and 6 and the highest permissible ethanol concentrations would be advantageous. This study has shown that the highly electronegative trifluoromethyl group at the 5 position increases the lability of a 1,2,3-oxdiazole compound.     

Preformulation Development of a Human Leukocyte Elastase Inhibitor for Oral Dosage

Abstract

WIN 64733 solubility and partition coefficients were determined with a precise and accurate HPLC method. Solubility decreased with increasing pH (140 mg/mL at pH 2.0, 86 mg/mL at pH 3.8, and 48 mg/mL at pH 5.2) but equilibrated within 30 hours. In purified water the maximum concentration was 102 mg/mL with pH 3.6. The maximum solubility in hydroxypropyl-beta-cyclodextrin (HP-β-CD) is only 43 mg/mL. However, unlike the water solution, the cyclodextrin preparation did not precipitate when added to 0.1 N HCl or 0.9% NaCl. The precipitated chloride salt of WIN 64733 is amorphous. Excess compound that was wetted, but not dissolved, formed liquid crystals.

In human gastric fluid (HGF), WIN 64733 did not decompose in the solid or liquid state for 2 hours, or precipitate from solution despite NaCl and HCl in the HGF. WIN 64733 solid is stable to heat (50°C), light (1000 ft-candles), humidity (75% RH), and heat plus humidity for 6 weeks. Solutions of WIN 64733 are unstable, with first-order decomposition rates that are light independent at pH's 2.0 to 6.6. Decomposition was more rapid at higher pH's and increased temperature. This occurred by hydrolysis of the ester linkage forming an N-hydroxymethyl fragment that subsequently decomposed to saccharin and formaldehyde, verified by the Hantzsch reaction.

Since solubility is high in water and HGF, dissolution in the gastric environment would favor absorption of an oral dose.     

Kinetic and Biopharmaceutical Study of an Antiviral Agent in Aqueous Vehicle and Human Gastric Fluid

WIN 54954 is an investigative antiviral compound that is insoluble in water and very unstable in acidic pH. Both factors can potentially limit in vivo absorption and availability. Degradation involves hydrolytic opening of the oxazoline ring, which results in loss of antiviral activities. The degradation product in acid is mostly an aminoethylester, WIN 55696, which further decomposes in basic medium into the hydroxyethylamide, WIN 55795. WIN 54954 decomposition in buffer solution is pH dependent and follows first-order kinetics. The stability half-life of WIN 54954 in 0.1 N hydrochloric acid is less than I hr at body temperature. A series of in vitro experiments were conducted to evaluate the stability of the drug in human gastric fluid (HGF) from volunteers. These studies demonstrate that the presence of digestive enzymes of HGF did not alter the nature of oxazoline ring opening substantially. The decomposition products identified were similar to products identified in in-vitro buffered solutions. The rate of decomposition is faster in genuine human gastric fluid than in 0.1 N HCl. Decomposition is also pH dependent and does not vary among individuals.     

Physicochemical characterization of rutaecarpine-loaded microemulsion system

To develop an o/w microemulsion system containing poorly water-soluble rutaecarpine, the solubility of rutaecarpine in water, ethanol, various oils, and surfactants were investigated. Among the surfactants and oils tested, Tween 20/PEG 400 and castor oil were chosen as the surfactant system and oil phase of the microemulsion, as rutaecarpine was most soluble in them, respectively. Pseudoternary phase diagrams were constructed to obtain the concentration range of oil, surfactant, and cosurfactant for microemulsion formation, and the stability test of rutaecarpine delivered by microemulsion formation was then evaluated. Pseudoternary phase diagrams show that the areas of microemulsion appeared at those with 0-20% Smix (PEG 400/Tween80 = 60/40), 64-81% water, and 10-20% oil. The rutaecarpine (300 µg/g)-loaded microemulsion composed of 10.8% PEG 400, 7.2% Tween 80, 20% caster oil, and 72% water was physically and chemically stable for at least 6 months. Thus, the microemulsion system composed of castor oil, PEG 400, Tween 80, and water could be a stable dosage form for rutaecarpine.     

Physicochemical Characterization of Rutaecarpine-Loaded Microemulsion System

To develop an o/w microemulsion system containing poorly water-soluble rutaecarpine, the solubility of rutaecarpine in water, ethanol, various oils, and surfactants were investigated. Among the surfactants and oils tested, Tween 20/PEG 400 and castor oil were chosen as the surfactant system and oil phase of the microemulsion, as rutaecarpine was most soluble in them, respectively. Pseudoternary phase diagrams were constructed to obtain the concentration range of oil, surfactant, and cosurfactant for microemulsion formation, and the stability test of rutaecarpine delivered by microemulsion formation was then evaluated. Pseudoternary phase diagrams show that the areas of microemulsion appeared at those with 0–20% Smix (PEG 400/Tween80 = 60/40), 64–81% water, and 10–20% oil. The rutaecarpine (300 µg/g)-loaded microemulsion composed of 10.8% PEG 400, 7.2% Tween 80, 20% caster oil, and 72% water was physically and chemically stable for at least 6 months. Thus, the microemulsion system composed of castor oil, PEG 400, Tween 80, and water could be a stable dosage form for rutaecarpine.     

Preformulation studies of novel 5′-O-carbonates of lamivudine with biological activity: solubility and stability assays

As a part of preformulation studies, the aim of this work was to examine the solubility and stability of a series of 5′-O-carbonates of lamivudine with proven antihuman immunodeficiency virus activity. Solubility studies were carried out using pure solvents (water, ethanol and polyethylene glycol 400 [PEG 400]), as well as cosolvents in binary mixture systems (water–ethanol and water–PEG 400). These ionizable compounds showed that their aqueous solubility is decreasing as the carbon length of the substituent moiety increases, but being enhanced as the pH was reduced from 7.4 to 1.2. Thus, 3TC-Metha an active compound of the series, with an intrinsic solubility at 25?°C of 17?mg/mL, was about 70 times more soluble than 3TC-Octa (0.24?mg/mL), and at pHs of 1.2, 5.8 and 7.4 had intrinsic solubilities of 36.48, 19.20 and 15.40?mg/mL, respectively. In addition, the solubility was enhanced significantly by using ethanol and PEG 400 as cosolvents. A stability study was conducted in buffer solutions at pH 1.2, 5.8, 7.4 and 13.0 and in human plasma at 37?°C. Stability-indicating high-performance liquid chromatography procedure was found to be selective, sensitive and accurate for these compounds and good recovery, linearity and precision were also observed.     

Microemulsion systems containing bioactive natural oils: an overview on the state of the art

Abstract

Natural oils are extremely complex mixtures containing compounds of different chemical nature. Some of them have physiological or therapeutic activities that may act either alone or in synergy. Therefore, they are used in the pharmaceutical, agronomic, food, sanitary and cosmetic industries. Today, the interest in bioactive natural oils is growing due to their immense potential to prevent and treat numerous human diseases. Formulation in microemulsions (MEs) containing natural oils appeared suitable to improve pharmaceutical and biopharmaceutical properties of bioactive compound derivatives from these oils. Microemulsion systems are thermodynamically stable, transparent, and are isotropic dispersions consisting of oil and water stabilized by an interfacial film of surfactants, typically in combination with a cosurfactant. They can protect labile compounds from premature degradation, control release, increase solubility and hence enhance the bioavailability of poorly bioavailable compounds. The aim of this work was to review the various advantages of bioactive compounds presented in natural oil loaded ME systems to be used as delivery systems. First, the state of the art of the parameters involved in the ME formation, including the basic concepts of the physicochemical formulation of the ME systems, and the main aspects of production and the energy responsible for their formation were reported. The second section describes the use of ME systems and reviews the recent applications of natural oil-loaded in the ME systems as the bioactive compound in the formulation.     

In situ fastening graphene sheets into a polyurethane sponge for the highly efficient continuous cleanup of oil spills

Oil sorbents are an attractive option for oil-spill cleanup as they may be used for collection and complete removal of oil without adversely affecting the environment.However,traditional oil sorbents exhibit low oil/water separation efficiency and/or low oil-sorpfion capacity.In this study,an ultra-high performance graphene/polyurethane (PU) sponge has been successfully obtained by in situ polymerization in the presence of graphene dispersed in N-methylpyrrolidone (NMP).During polymerization,the NMP/graphene dispersion not only serves as a weak amine catalyst for the formation of the sponge,but promotes fixation of the graphene sheets in the framework of the PU sponge owing to the strong dipole interaction between NMP and graphene.The as-prepared graphene/PU sponge was used as an absorbing material for the continuous removal of oil from oil-spill water.The graphene/PU sponge can continuously and rapidly remove oils from immiscible oil/water mixtures in corrosive solutions,including strong acids and bases,hot water,and ice water,with an excellent separation efficiency of above 99.99％.In addition,the as-prepared graphene/PU sponge was effective in separating surfactant-stabilized emulsions with a high separation efficiency of ＞99.91％.     

Superhydrophobic silica wool—a facile route to separating oil and hydrophobic solvents from water

Silica microfiber wool was systematically functionalized in order to provide an extremely water repellent and oleophilic material. This was carried out using a two-step functionalization that was shown to be a highly effective method for generating an intense water repulsion and attraction for oil. A demonstration of the silica wools application is shown through the highly efficient separation of oils and hydrophobic solvents from water. Water is confined to the extremities of the material, while oil is absorbed into the voids within the wool. The effect of surface functionalization is monitored though observing the interaction of the material with both oils and water, in addition to scanning electron microscope images, x-ray photoelectron spectroscopy and energy dispersive x-ray analysis. The material can be readily utilized in many applications, including the cleaning of oil spills and filtering during industrial processes, as well as further water purification tasks—while not suffering the losses of efficiency observed in current leading polymeric materials.     

聚烯烃抗氧剂1076和168在食用油中的迁移研究

借助HPLC分析仪器试验研究了不同温度下聚烯烃抗氧剂1076和168向食用调和油、玉米油和菜籽油的迁移,讨论了不同油类、温度对迁移的影响,并将所得结果与用100%乙醇作为脂肪模拟物取得的结果进行对比.结果表明:油的种类对抗氧剂的迁移过程影响较小;温度对迁移动力学过程起到决定性作用,迁移速度随温度的升高而加快,达到迁移平衡所需的时间也越短;2种抗氧剂在食用油和100%乙醇中的迁移行为相似,总体说来100%乙醇可以作为脂肪模拟物来替代食用油用于抗氧剂的迁移试验研究.     

Comparing ignitability for in situ burning of oil spills for an asphaltenic,a waxy and a light crude oil as a function of weathering conditions under arctic conditions

In situ burning of oil spills in the Arctic is a promising countermeasure. In spite of the research already conducted more knowledge is needed especially regarding burning of weathered oils. This paper uses a new laboratory burning cell (100 mL sample) to test three Norwegian crude oils, Grane (asphalthenic), Kobbe (light oil) and Norne (waxy), for ignitability as a function of ice conditions and weathering degree. The crude oils (9 L) were weathered in a laboratory basin (4.8 m³) under simulated arctic conditions (0, 50 and 90% ice cover). The laboratory burning tests show that the ignitability is dependent on oil composition, ice conditions and weathering degree. In open water, oil spills rapidly become “not ignitable” due to the weathering e.g. high water content and low content of residual volatile components. The slower weathering of oil spills in ice (50 and 90% ice cover) results in longer time-windows for the oil to be ignitable. The composition of the oils is important for the window of opportunity. The asphalthenic Grane crude oil had a limited time-window for in situ burning (9 h or less), while the light Kobbe crude oil and the waxy Norne crude oil had the longest time-windows for in situ burning (from 18 h to more than 72 h). Such information regarding time windows for using in situ burning is very important for both contingency planning and operational use of in situ burning.     

Screening of oil samples on the basis of excitation-emission room-temperature phosphorescence data and multiway chemometric techniques. Introducing the second-order advantage in a classification study

Room-temperature phosphorescence excitation-emission matrices and multiway methods have been analyzed as potential tools for screening oil samples, based on full matrix information for polyaromatic hydrocarbons. Crude oils obtained from different sources of similar geographic origin, as well as light and heavy lubricating oils, were analyzed. The room-temperature phosphorescence matrix signals were processed by applying multilayer perceptron artificial neural networks, parallel factor analysis coupled to linear discriminant analysis, discriminant unfolded partial least-squares, and discriminant multidimensional partial least-squares (DN-PLS). The ability of the latter algorithm to classify the investigated oils into four categories is demonstrated. In addition, the combination of DN-PLS with residual bilinearization allows for a proper classification of oils containing unsuspected compounds not present in the training sample set. This second-order advantage concept is applied to a classification study for the first time. The employed approach is fast, avoids the use of laborious chromatographic analysis, and is relevant for oil characterization, identification, and determination of accidental spill sources.     

Some Formulation Properties of Lapachol,A Potential Oncolytic Agent of Natural Origin

Abstract

Lapachol is a naphthaquinone of natural origin with reported oncolytic activity. However, earlier antitumor studies were inhibited by inadequate blood levels, allegedly due to formulation difficulties.

This present study shows that water solubility is markedly influenced by pH, varying from 1.5 μg/mL at pH 4.0 to 5 mg/mL at pH 10.0.

Evaluation of mixed solvent systems demonstrated that up to 30 mg/mL could be dissolved in polyethylene glycol (PEG) 400. Aqueous PEG 400 solutions of lapachol were stable at refrigerator temperatures but deteriorated when exposed to light or autoclaving. Aqueous ethanol or propylene glycol are realistic alternative solvent systems for injectable lapachol solutions that may be sterilized by autoclaving.

Phosphatide stabilized triglyceride emulsions are broken down by lapachol, suggesting an interfacial interaction between the phosphatide and the lapachol in the aqueous phase.     

Synthesis of pH-sensitive water and oil dual-absorption material using microemulsion polymerization process

pH-sensitive water and oil dual-absorption material (WODAM) has been successfully synthesized through microemulsion polymerization. Firstly, microemulsions prepared with monomers were analyzed by pseudo-ternary phase diagram. In addition, conductivities of microemulsions were tested to identify microemulsion types. Meanwhile, the factors that affected microemulsion types were analyzed. Then WODAMs were prepared, and the chemical structure was characterized using Fourier transform infrared (FTIR) spectroscopy. Liquid absorption tests indicated that both monomer ratio and microstructure of WODAMs had influences on their water absorption rate (WAR) and oil absorption rate (OAR). In addition, pH sensitivity tests showed that WODAM absorbed much water in neutral and weak alkaline solutions, but little water in strong alkaline solutions. What’s more, liquid absorption tests in cement slurry filtrate (CSF) showed that WODAM was applied to oil well cement. This paper prepared a new self-healing agent, and is of great significance to realize self-healing cement in complex downhole condition.     

Some Formulation Properties of Lapachol, A Potential Oncolytic Agent of Natural Origin

Lapachol is a naphthaquinone of natural origin with reported oncolytic activity. However, earlier antitumor studies were inhibited by inadequate blood levels, allegedly due to formulation difficulties.

This present study shows that water solubility is markedly influenced by pH, varying from 1.5 μg/mL at pH 4.0 to 5 mg/mL at pH 10.0.

Evaluation of mixed solvent systems demonstrated that up to 30 mg/mL could be dissolved in polyethylene glycol (PEG) 400. Aqueous PEG 400 solutions of lapachol were stable at refrigerator temperatures but deteriorated when exposed to light or autoclaving. Aqueous ethanol or propylene glycol are realistic alternative solvent systems for injectable lapachol solutions that may be sterilized by autoclaving.

Phosphatide stabilized triglyceride emulsions are broken down by lapachol, suggesting an interfacial interaction between the phosphatide and the lapachol in the aqueous phase.     

Stability of penethamate,a benzylpenicillin ester prodrug,in oily vehicles

Penethamate (PNT) is an ester prodrug of benzylpenicillin which is marketed as dry powder for reconstitution with aqueous vehicle prior to injection. The purpose of this paper was to investigate the chemical stability of PNT in oily formulations to provide a basis for a ready-to-use (RTU) oil-based PNT formulation. The chemical stability of PNT solutions and suspensions in light liquid paraffin (LP), medium chain triglyceride (MIG), ethyl oleate (EO) and sunflower oil (SO) was investigated at 30?°C. Solid state stability of PNT powder and stability of PNT in EO suspensions with different moisture contents were also evaluated. The solubility of PNT in the oils was in order SO?>?EO?>?MIG?>?LP. Degradation of PNT was rapid in oily solutions and less than 10% remained after 7–15 days. Stability of PNT decreased with increase in moisture content in ethyl oleate suspensions. PNT was stable over four weeks in the solid state. Hydrolysis, due to moisture in the oil formulation is not the only degradation mechanism. PNT stability (% drug remaining) in oily suspensions after 3.5 months was in the order LP (96.2%)?>?MIG (95.4%)?>?EO (94.1%)?>?SO (86%). A shelf-life of up to 5.5 years at 30?°C may be achieved for PNT suspension in these oils.     

Colloidal Properties of Crude Oils Studied by Dynamic Light-Scattering

Colloidal properties and kinetics of asphaltene aggregation in three crude oils using a dynamic light-scattering method adapted to opaque fluids were investigated. The technique makes it possible to measure the size of particles suspended in nearly nontransparent liquid media. The studied native crude oils were found to have persisting colloidal particles. The observed particles are assumed to be asphaltene/resin aggregates. Using n-heptane as a precipitant, asphaltene aggregation kinetics in crude oils was studied. Experimental measurements of the particle size as a function of time in solutions with different oil/precipitant ratios are reported. The aggregation kinetics accelerates with increasing precipitant concentration. The oil sample with a large amount of paraffins is on the edge of instability and exhibits a slow asphaltene aggregation process without precipitant. Aggregation in the two other oils starts only at some threshold concentration of the precipitant, lasts a short time, and results in the formation of stable-in-size particles. The results obtained prove that dynamic light scattering is an effective method to test petroleum colloid stability.     

Water-Soluble Anisotropic Iron Oxide Nanoparticles: Dextran-Coated Crystalline Nanoplates and Nanoflowers

We report a simple phase transfer based synthesis route for two novel anisotropic water soluble iron oxide nanoparticle shapes, namely, nanoplates and nanoflowers. The nanoplates and nanoflowers are initially prepared in an organic solvent via a modified “heat-up” method. Then, the crystalline nanoparticles are rendered hydrophilic via sonication in the presence of dextran and water. These nanoparticles are highly monodisperse and superparamagnetic at room temperature. High resolution transmission electron microscopy indicates that the iron oxides cores are not affected by the phase transfer. Dextran coating is confirmed by dynamic light scattering, Fourier transform infrared spectroscopy, and thermogravimetric analysis. The obtained dextran coverage was 26 wt% for the nanoplates and 37 wt% for the nanoflowers. The nanoplates and nanoflowers were not only water soluble, but also remained stable at different pH (4–7) and in common aqueous buffer solutions. Thorough characterizations of the nonspherical iron oxide nanoparticles indicate that these particles could be useful for potential biomedical applications and magnetic resonance imaging.