Salol Research Articles

Improving Zonisamide Manufacturing: Insights into Stereochemistry and Mechanisms for Continuous Optimization

Zonisamide is a heterocyclic sulfonamide widely employed as anticonvulsant. In this work, we report an efficient process for the preparation of zonisamide, obtained in a six‐step synthesis from phenyl salicylate with an overall 31% yield. The key step is represented by a base‐promoted intramolecular rearrangement of a β‐ketosultone oxime, leading to the concomitant formation of the benzisoxazole ring and of the exocyclic sulfonic group. This intriguing transformation is investigated with a combination of analytical techniques (NMR, HRMS, PXRD), leading to a preliminary mechanistic proposal.

Supplemental Patch Testing Identifies Allergens Missed by Standard Screening Series.

Background: Supplemental patch testing is an adjunct to standard patch test screening series. Objective: To determine the demographics, characteristics, frequency, relevance, and interpretation of patch test reactions for supplemental patch testing. Methods: Retrospective study of patients tested 2017-2020 with North American Contact Dermatitis Group (NACDG) and supplemental screening series (Supplemental Series A [SSA], Supplemental Series B [SSB]). Demographics, characteristics, reaction strengths, relevance, and final interpretation were recorded. Results: Cohort included 791 patients; 73.5% female, 68.6% age >40 years. 74.1% were White, 15.2% Black, 5.7% Asian, and 1.5% Hispanic. The most common Dermatitis sites were scattered/generalized (27.2%), face (24.0%), and hands (23.5%). For 2017-2018 and 2019-2020, respectively, 82% (318/388) and 78.4% (316/403) had ≥1 "allergic" reaction. In addition, 13.5% (52/385) and 11.7% (47/403) had SSA reactions, and 38.1% (115/302) and 31.5% (101/321) had SSB reactions. In the 87 (2017-2018) and 99 (2019-2020) patients with negative NACDG testing, 17 (19.5%) and 12 (12.1%) had supplemental reactions. Of the 34 supplemental allergens with reaction frequency ≥1%, 58.8% (20/34) are not part of the American Contact Dermatitis Society 90 (2020) or NACDG 2021-2022 screening series. The highest frequency allergens from this group were dodecyl and octyl gallate, cinnamic alcohol, phenyl salicylate, hexahydro-1,3,5-tris-(2-hydroxyethyl) triazine, and abitol. Conclusions: Supplemental patch testing identifies additional relevant allergens in patients with suspected allergic contact Dermatitis.

Porous SiO2 antireflection film with high UV resistance

Sol-gel is one of the most economical methods to prepare antireflection films, but the low ultraviolet radiation-resistance (UV-resistance) of the sol-gel film limits its applicability in the solar industry. A SiO2 antireflection film was prepared with sol-gel method with phenyl salicylate (PS) as the porogen. The effects of the PS addition were investigated on the microstructure, optical property and UV-resistance of the film. When the addition of PS is 1.20 g, the refractive index at 550 nm is 1.30, and the maximum transmittance is 96.30 %. The average transmittance within the 400–1100 nm range reaches its peak at 92.85 %, which is 4.35 percentage points higher than that of the blank glass. In addition, the film without PS has an average transmittance of 91.00 % after 5000 equivalent solar hours (ESHs) UV irradiation, decreasing 1.07 percent point, and has a pencil hardness of 5 H and an adhesion of grade 2 of the tape-tearing method. However, the film with 1.20 g of PS still has an average transmittance of 92.15 % after 5000 ESHs UV irradiation, decreasing only 0.7 percent point, and has a pencil hardness of 7 H and an adhesion of grade 1 of the tape-tearing method.

Temperature-switchable deep eutectic solvent extraction of polysaccharides from wolfberry fruits: Process optimization, structure characterization, and antioxidant activity

Polysaccharides of wolfberry (LBPs) with complex structures are most commonly used in the food and pharmaceutical industries as biologically active phytochemicals. However, the structure and yield of LBPs vary according to the extraction method used, and selecting their extraction media remains difficult. A novel type of temperature-switchable deep eutectic solvent (TS-DES), consisting of L-menthol and phenyl salicylate, was designed to extract LBPs from wolfberry fruits. TS-DES was a recyclable extractant above the maximum critical solution temperature (UCST). The increased dispersibility of extraction solvents was imparted by combining them with a high-speed shear dispersion emulsification (HSDE) machine. TS-DES was in full contact with the cell walls of wolfberries, leading to the complete opening of the cell walls, resulting in the efficient extraction of LBPs. Compared with traditional extraction, the yield of LBPs-D reached 4.35%, which was higher than that of LBPs-W (1.78%). This study showed that LBPs-D were high molecular weight, highly branched polysaccharides with antioxidant activity. TS-DES was separated at a lower level than UCST for regeneration and reuse. After 5 cycles, TS-DES still had excellent recovery and extraction performance. This study provides valuable information for efficiently extracting structurally rich bioactive polysaccharides from plants using TS-DES.

Deep eutectic solvents formed by pharmaceutical ingredients and their potential influences on solid preparations

Some active pharmaceutical ingredients (APIs) and excipients can form deep eutectic solvents (DESs), which will lead to severe defects in solid preparations. This work first prepared related typical DESs by mixing APIs and excipients from marketable drugs. Then two different types of the binary eutectic mixtures were investigated, which were composed of menthol (HBD) and citric acid (HBA) (ME/CA) as well as phenyl salicylate (HBA) and benzoic acid (HBD) (Salol/BA). These binary mixtrures were applied to investigate their possible effects on capsules and tablets, which could be liquefaction or the stickiness of the solid formulations. The comprehensive characterizations and studies on phase behaviors of the binary mixtures were carried out, and the spectral analysis confirmed the formation of the eutectic liquids from individual components. Furthermore, the binary mixtures have increased the tablet strength when increasing the compression force, leading to the stickiness of powders during pressing. Moreover, the capsules were softened by the existence of DESs. After morphological observation and quantitative analysis, the corresponding suggestions and countermeasures were provided in the conclusions.

Viscoelasticity of Liposomal Dispersions.

Janus-faced viscoelastic gelling agents-possessing both elastic and viscous characteristics-provide materials with unique features including strengthening ability under stress and a liquid-like character with lower viscosities under relaxed conditions. The mentioned multifunctional character is manifested in several body fluids such as human tears, synovial liquids, skin tissues and mucins, endowing the fluids with a special physical resistance property that can be analyzed by dynamic oscillatory rheology. Therefore, during the development of pharmaceutical or cosmetical formulations-with the intention of mimicking the physiological conditions-rheological studies on viscoelasticity are strongly recommended and the selection of viscoelastic preparations is highlighted. In our study, we aimed to determine the viscoelasticity of various liposomal dispersions. We intended to evaluate the impact of lipid concentration, the presence of cholesterol or 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and the gelling agents polyvinyl alcohol (PVA) and hydroxyethylcellulose (HEC) on the viscoelasticity of vesicular systems. Furthermore, the effect of two model drugs (phenyl salicylate and caffeine) on the viscoelastic behavior of liposomal systems was studied. Based on our measurements, the oscillation rheological properties of the liposomal formulations were influenced both by the composition and the lamellarity/size of the lipid vesicles.

Hydroxyl-directed C–C bond activation of benzophenones for the O-acylation of phenols

We report that 2-hydroxyl benzophenones can be converted to phenyl salicylate esters by loss of an aryl group and O-acylation of the phenols. Iridium, cyclooctadiene, and bulky monodentate phosphine ligands catalyze the ketone C–C bond activation and fragmentation. We identified common side products in this process, which include C-acylation of the phenol reactant or trapping on cyclooctadiene. Several of the processes reported here appear to be under equilibrium control. Overall, our report provides insight into the activation and functionalization of unstrained C–C bonds with group 9 catalysts.

Development and characterization of biodegradable ultraviolet protective and antibacterial polylactic acid-cellulose acetate film modified by phenyl salicylate

The polylactic acid composite films were successfully fabricated via the technique of solvent casting using cellulose acetate (20%, wt) as the reinforcing material and phenyl salicylate as the ultraviolet (UV) absorbent and antibacterial agent. Polylactic acid-cellulose acetate-phenyl salicylate composite films displayed complete absorption effect at the region of UV-C (280–100 nm) and UV-B (315–280 nm), and more than 95% UV absorption effect at the region of UV-A (400–315 nm). These results indicate that the UV shielding performance of the composite films could be significantly improve by addition of phenyl salicylate. Moreover, the addition of 20% phenyl salicylate could improve the steam resistance, mechanical properties and thermal stability of the films, and the composite films had also better antibacterial activity against Escherichia coli. The composite films could reduce the decay rate of fresh lilies and extend their storage time. The degradation characteristics of the films were explored in the natural environment and the laboratory level, which provided application prospect for the development of degradable food packaging materials with anti-ultraviolet and anti-bacteria effect.

SCIENTIFIC BASIS OF THE USE OF SALICYLATES IN ADAPTIVE TECHNOLOGIES OF SPRING BARLEY CULTIVATION

The article scientifically substantiates the use of an exogenous plant metabolite, salicylic acid (SA), as an inducer of nonspecific acquired resistance in spring barley plants. Under a greenhouse experiment, a positive effect of a protective and stimulating composition based on salicylate on the parameters of growth and development of spring barley plants infected with the fungus B. sorokiniana, and the degree of their infection with a fungal disease - dark brown spotting, was revealed. Under field conditions, the stimulating effect of SA and phenyl salicylate on growth processes, the content of photosynthetic pigments in the leaf, the activity of lipid peroxidation and peroxidase in plant cells was shown. An increase in the overall resistance of spring barley plants in crops to unfavorable environmental factors, including phytopathogens, was established, which ultimately ensured the formation of a crop at the level of the standard fungicide Adexar with an increase of 4-5 centners for hectare compared to the untreated control. On the basis of the results obtained, the immunomodulatory drug “Immunakt-SA” was developed, which is a composition of SA and a water-soluble polymer VSP-3. The use of the drug ensures stable yields of barley grain at the level of standard chemical fungicides, which in the future will significantly reduce the use of expensive chemicals for plant protection and the chemical load on the environment.

Experimental Research on the Temperature Characterization of a Miniature Phase Change Cells in the Blackbody for the On-Orbit Radiometric Calibration of Thermal Infrared Sensors

For on-orbit radiometric calibration of infrared (IR) satellite instruments, we have developed a blackbody source whose temperature can be accurately determined by use of miniature phase change cells to provide fixed points. The temperatures and reproducibility of six phase change cells containing H <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> O, Ga–Sn alloy, Ga–Zn alloy, phenyl salicylate (PS), succinonitrile, and Ga were accurately determined by the measurement of the phase change plateaux. The points were measured using the quasiadiabatic vacuum measurement system, which was developed by the National Institute of Metrology, China. The reproducibility time span of the Ga fixed point was as long as six years. Results indicated that the reproducibility values of multiple phase-change run-off point temperatures of H <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> O, Ga–Sn alloy, Ga–Zn alloy, PS, succinonitrile, and Ga were 2.0, 3.6, 1.5, 3.5, 2.9, and 3.1 mK, respectively. Furthermore, a strong linear relation was observed between the heating power and the run-off temperature. With decreasing heating power, the temperature of the plateau decreased and approached the defined fixed-point value. All simulation results of the miniature fixed points were consistent with the experimental data.

DSC temperature calibration over the range −125 °C to 50 °C

The lack of Nationally Certified Reference Materials for the calibration of DSC equipment in the sub-ambient range has been addressed by the introduction of a Certified Reference Material of purified cyclohexane by the National Metrology Institute of Japan. This sample, in conjunction with the CRM material phenyl salicylate and the ITS-90 fixed point material mercury, has enable a DSC-thermomicroscopy system to be accurately calibrated over the temperature range −90 °C to 50 °C. The DSC has then been used to measure values for the solid-solid transitions in the potential Certified Reference Materials ammonium sulphate, adamantane and ammonium dihydrogen phosphate, which have the advantage of being thermally stable and easy to handle, and for the melting point of diphenyl ether. In addition, the effect of temperature cycling on these materials has been investigated.

Spaceborne radiance temperature standard blackbody for Chinese high-precision infrared spectrometer

As a radiance temperature standard source for the Chinese high-resolution spectrum infrared spectrometer, the National Institute of Metrology, China, developed a spaceborne radiance temperature standard blackbody (SRTSB) combined with a series of miniature phase change fixed points (MPCFPs) for temperature calibration and emissivity verification using a thermal radiation loop (TRL). The MPCFPs of the SRTSB contain H2O, Ga, Ga–Sn alloy, and phenyl salicylate. The TRL is used to measure the emissivity of the spaceborne blackbody on the basis of controlling environmental radiation. Experimental results show that the blackbody emissivity is higher than 0.998 and the temperature control stability is better than 5 mK. Temperature control uniformity at the cavity bottom and axial are better than or equal to 11 mK and 38 mK, respectively, in the working temperature range of 268.15 K to 331.15 K.. The repeatability of the MPCFPs is less than 5 mK, and the results of the continuous phase transition of the MPCFPs are in a clear temperature plateau. The expanded uncertainty of the SRTSB is lower than or equal to 0.084 K (k = 2).

ДОСЛІДЖЕННЯ ВПЛИВУ СВІТЛОСТАБІЛІЗАТОРІВ НА СВІТЛОСТІЙКІСТЬ ЗАБАРВЛЕНОГО АКТИВНИМИ БАРВНИКАМИ БАВОВНЯНОГО ТРИКОТАЖУ

The goal of the work is to study the effect of light stabilizers on the lightfastness of colours of cotton knit fabric dyed with reactive dyes. The study was carried out using a cotton 1+1 rib knit fabric with a surface weight of 150 g/cm2, prepared by the combined technology of boiling and bleaching. Dyeing of the fibrous material was carried out using Bezaktiv reactive dyes in a batch method at a concentration of 0.3% by weight of the material. UV absorbers 2,5-dihydroxyacetophenone, 2,4-dihydroxybenzophenone, phenyl salicylate and antioxidants – diatomic phenols – hydroquinone, pyrocatechol and resorcinol were chosen as light stabilizers. In the work, the light stabilization of cotton knit fabric was carried out after dyeing with reactive dyes and washing the dyed knit material. The technological mode of application of the studied light stabilizers was to impregnate a knit fabric, drying and curing the material. The individual effect of light stabilizers on the colour change of dyed knit fabric samples and the photodestruction kinetics of dyes were investigated. The insolation of the samples was carried out on a device with a mercury-tungsten lamp RF 1201 BS ("REFOND"). After treatment and insolation, the total colour difference dE of knit samples were determined compared to untreated material using a TCR-200 colorimeter ("PCE Instruments"). The results obtained indicate that the change in the initial colours after treatment with light stabilizers depends on the colour of the dye and on the type of light stabilizer. The greatest colour changes are observed with phenyl salicylate, pyrocatechol and resorcinol. It has been established that UV absorbers exhibit a light-shielding effect to a greater extent than antioxidants. The obtained experimental results also indicate the need for the simultaneous use of UV absorbers and antioxidants in order to efficiently stabilize dyed cotton knit fabric. The individual effect of light stabilizers – UV absorbers and antioxidants – on the lightfastness of colours of cotton knit fabric dyed with Bezaktiv reactive dyes is investigated. It was established that for effective light protection of colours of cotton knit fabric dyed with reactive dyes, the simultaneous use of UV absorbers and antioxidants is necessary

Temperature-controlled liquid–liquid microextraction using a biocompatible hydrophobic deep eutectic solvent for microextraction of palladium from catalytic converter and road dust samples prior to ETAAS determination

A simple method based on temperature-controlled liquid–liquid microextraction (TC-LLME) using a novel hydrophobic deep eutectic solvent (DES) was developed for preconcentration of palladium. Deep eutectic solvent based on phenyl salicylate (salol) and DL-menthol (1:1) was used as the extraction solvent. The control of temperature enhanced the dispersion of deep eutectic solvent and a homogeneous solution was made. Upon cooling the solution in an ice bath, a cloudy solution was formed. Afterwards, the mixture was centrifuged and the sediment phase was analyzed by Electrothermal Atomic Absorption Spectroscopy (ETAAS). To improve the extraction efficiency, the main parameters were optimized. Under the optimized extraction conditions, the limit of detection (LOD) and limit of quantification (LOQ) were 0.03 μg L−1 and 0.10 μg L−1 respectively. Preconcentration factor was obtained 191. The precision, expressed as the relative standard deviation (RSD, n = 10), found to be 4.6%. Finally, the method was an effective procedure for the determination of palladium in water, catalytic converter and road dust samples with acceptable extraction recoveries of 95.1% to 100.4%. The obtained results confirmed the ability of the developed method in the different samples.

Development and Validation of a Gas Chromatographic Method for Quantitative Determination of the Active Ingredient in Phenyl Salicylate Drug Substance

Anew method for quantitative determination of the active ingredient in phenyl salicylate drug substance using gas chromatography with flame-ionization detection (GC-FID) was developed and validated. The experiments used an HP-5 quartz capillary column with a grafted stationary phase of diphenyl- (5%) and dimethylpolysiloxane (95%) (Agilent Technologies, USA). The conditions for the chromatographic separation and the chromatography system suitability parameters were determined. The phenyl salicylate content in the drug substance was determined by the internal standard method. The method was validated for specificity, linearity, precision, and stability (robustness) and was found to meet the main acceptance criteria.

Комплексный анализ применения фитопрепарата «пародонтоцид» в консервативном лечении больных хроническим генерализованным пародонтитом легкой степени

A comprehensive clinical and laboratory analysis of the use of the phytoremedy «Parodontocide» in the complex treatment of chronic periodontitis was carried out. «Parodontocide» contains sage oil, peppermint oil, sage oil, clove oil, allantoin, phenyl salicylate and it demonstrates a pronounced anti-inflammatory and repairing effect. It was well tolerated by the majority of patients, practically causing no adverse reactions and complications in comparison with other medications. That's precisely why «Parodontocide» can be used in a comprehensive treatment program for mild chronic periodontitis and in patients with intolerance to synthetic antiseptics as a part of monotherapy.

Разработка и валидация методики количественного определения действующего вещества в субстанции фенилсалицилата методом газожидкостной хроматографии

Целью исследования являлась разработка и валидация новой методики количественного определения действующего вещества в субстанции фенилсалицилата методом газожидкостной хроматографии с пламенно-ионизационным детектированием (ГХ/ПИД). Исследования выполнены на капиллярной кварцевой колонке HP-5 с химически привитой фазой: 5 % дифенил, 95 % диметилполисилоксан («Agilent Technologies» США), разработаны условия хроматографического разделения. Определены параметры пригодности хроматографической системы. Содержание фенилсалицилата в субстанции определяли по методу внутреннего стандарта. Валидационную оценку методики проводили по показателям: специфичность, линейность, прецизионность, устойчивость (робастность). Установлено ее соответствие основным критериям приемлемости.

Stir bar sorptive extraction and automatic two-stage thermal desorption-gas chromatography-mass spectrometry for trace analysis of the byproducts from diphenyl carbonate synthesis

In this study, a fast and sensitive method based on stir bar sorptive extraction (SBSE) and two-step thermal desorption coupled with online gas chromatography-mass spectrometry was established to simultaneously analyse six trace byproducts [phenyl salicylate (PS), xanthone (XA), methyl o-hydroxybenzoate (MS), 2-methyl diphenyl carbonate (PTC), methyl o-methoxybenzoate (MSME) and phenyl o-methoxybenzoate (PSME)] generated in the process of diphenyl carbonate (DPC) synthesis. Analytes were enriched with multiple sorptive stir bars simultaneously, followed by thermal desorption, cryo-focusing, and instantaneous injection, effectively solving such problems as long adsorption time and small sample volumes compared with conventional stir bars. The main factors influencing SBSE and thermal desorption were studied. Optimized stir bar extraction conditions are as follows: the volume fraction of methanol is 10%, the extraction time is 6 min, and the stirring rate is 1200 rpm at room temperature (25 °C). Optimized two-step thermal desorption conditions are as follows: in the first desorption step, the desorption temperature is 300 °C, the desorption time is 10 min, and the valve and transmission line temperature is 200 °C; in the second desorption step, the cold trap temperature is −10 °C, which is increased at a rate of 100 °C/s to 320 °C and held for 5 min. A splitless mode and a split mode with a split ratio of 20:1 are used in the first and the second desorption step, respectively. Under the optimal conditions, the six byproducts generated in the synthesis of DPC via transesterification were quantitatively analyzed by external standard method. The results showed that, within the range of 1.0−100 ng/L for all of the six transesterification byproducts, this method revealed good linearity with correlation coefficients (r) ≥0.997. The limits of detection (LODs) were between 0.054 ng/L and 0.253 ng/L, the relative standard deviations (RSD) were from 5.2% to 11.5%, and the recoveries were 81.6%−102.6% (n = 3). The method is simple, rapid and has a wide linear range, high accuracy, and sensitivity, as well as good stability. It is suitable for simultaneous, rapid and selective analysis of six trace byproducts in the process of DPC synthesis. It can also provide vigorous data support and industrialization guidance for the selection of transesterification conditions and research on the formation mechanisms, distribution regularity, and even control of transesterification byproducts.

Qualitative and Quantitative Analysis of the Product and By-Products from Transesterification between Phenol and Dimethyl Carbonate.

By-products (phenyl salicylate, phenyl 4-hydroxybenzoate, and xanthone) from transesterification between phenol and dimethyl carbonate (DMC) were qualitatively analyzed by gas chromatography-mass spectrometry, and a gas chromatographic method with directed injection for simultaneous quantitative analysis of the product (DPC) and by-products of the transesterification has been established. Based on the results of qualitative and quantitative analyses, the mechanism of the by-products generation was preliminarily deduced. The sample for quantitative analysis was directly diluted in acetone, and related compounds were separated on an HP-5 capillary column and detected by a hydrogen flame ionization detector (FID). The product and by-products were well separated, the correlation coefficients (r) within the concentration range of 1.0 μg/mL–100 μg/mL were ≥0.9997, the relative standard deviations were between 0.5% and 4.4%, spiked recoveries were between 91.5% and 105.6%, and detection limits were between 0.11 and 0.18 μg/mL. The established method is simple, rapid, accurate, sensitive, and highly specific. It is suitable for simultaneous qualitative and quantitative analyses of the product and by-products of transesterification between phenol and DMC.

Influence of coordinating groups of organotin compounds on the Fries rearrangement of diphenyl carbonate.

In this paper, the Fries rearrangement of diphenyl carbonate (DPC) catalyzed by organotin compounds with different coordination groups was studied for the first time. The electronic effect and steric hindrance of the coordinating groups were discussed with respect to the reactivity of DPC rearrangement. The results showed that both the electronic effect and steric hindrance of the coordinating groups influenced the acidity of the active tin centers and then affected the catalytic performance of organotin as a Lewis acid for the rearrangement of DPC, and the influence of the electronic effect is greater than that of steric hindrance. The catalytic activity is in the order of BuSnO(OH) > Bu2SnO > Bu2Sn(OCOC11H23)2 > BuSnCl3 > Bu3SnOSnBu3 > Bu3SnCl, and Bu2SnO showed the best catalytic activity due to its strong electron absorption effect, small steric hindrance, and good stability. Under the optimum reaction conditions, the conversion of DPC was up to 93%, and the yields of phenyl salicylate (PS) and xanthone (XA) were 62% and 28%, respectively. In addition, a reaction mechanism of DPC rearrangement catalyzed by the organotin compounds was speculated. This research can provide vigorous theoretical data support to control the byproducts produced by DPC rearrangement in the process of DPC synthesis. It also provides a new route for the preparation of PS and XA.