Detailed Visualization of Aromaticity Using Isotropic Magnetic Shielding.

For many years, Clar's aromatic sextet theory has served as a qualitative method for assessing the aromatic character of polycyclic aromatic hydrocarbons. A new approach, based on the calculation of isotropic magnetic shielding (IMS) contour plots, is shown to provide a feature-rich picture of aromaticity that is both quantitative yet still easily interpreted. Chemists are visual creatures who are adept at discerning reactivity and chemical behavior from molecular structures. To quote Roald Hoffmann, "People like pictures. Chemists live off them." Thus, the detailed image analysis we present simultaneously provides quantitative assessment of electronic structure, which is still easy-to-understand through visual inspection, embedded in an aesthetically appealing and intuitive picture that draws the reader in. We provide novel computed IMS contour plots for a representative selection of aromatic molecules. Where Clar's static drawings capture only a partial sketch of the electronic properties of a molecule, IMS contour plots present a detailed, global landscape of a molecule that sums all possible resonance structures. This novel analysis allows us to correct certain drawbacks of Clar's analysis with respect to polycyclic aromatics and quantitatively assess the bonding and electronic structure of acene hydrocarbons.

Drug-related deaths in Scotland 1979-2013: evidence of a vulnerable cohort of young men living in deprived areas.

BACKGROUND: Even after accounting for deprivation, mortality rates are higher in Scotland relative to the rest of Western Europe. Higher mortality from alcohol- and drug-related deaths (DRDs), violence and suicide (particularly in young adults) contribute to this 'excess' mortality. Age-period and cohort effects help explain the trends in alcohol-related deaths and suicide, respectively. This study investigated whether age, period or cohort effects might explain recent trends in DRDs in Scotland and relate to exposure to the changing political context from the 1980s. METHODS: We analysed data on DRDs from 1979 to 2013 by sex and deprivation using shaded contour plots and intrinsic estimator regression modelling to identify and quantify relative age, period and cohort effects. RESULTS: The peak age for DRDs fell around 1990, especially for males as rates increased for those aged 18 to 45 years. There was evidence of a cohort effect, especially among males living in the most deprived areas; those born between 1960 and 1980 had an increased risk of DRD, highest for those born 1970 to 1975. The cohort effect started around a decade earlier in the most deprived areas compared to the rest of the population. CONCLUSION: Age-standardised rates for DRDs among young adults rose during the 1990s in Scotland due to an increased risk of DRD for the cohort born between 1960 and 1980, especially for males living in the most deprived areas. This cohort effect is consistent with the hypothesis that exposure to the changing social, economic and political contexts of the 1980s created a delayed negative health impact.

Box-Behnken experimental design for preparation and optimization of the intranasal gels of selegiline hydrochloride.

Selegiline hydrochloride (SL) is chosen as an adjunct for the control of clinical signs of Parkinsonian patients. The aim of the present work is to develop and optimize thermosensitive gels using Pluronic (F-127) for enhancing transport of SL into the brain through the nasal route. SL gels were prepared using a cold method and the Box-Behnken experimental design methodology. Drug (SL), gelling agent (F-127), and emulsifier (Propylene glycol, PG) were selected as independent variables, while the gelation temperature, gel strength, pH, gel content, and gel erosion were considered as dependent variables. For further understanding of the interaction between the various variables, contour plots and surface plots were also applied. Selected formulations, like S10 (contain 25 mg SL, 20 g F-127, and 1 g PG) and S14 (contain 50 mg SL, 18 g F-127 and 1 g PG), had a clear appearance in the sol form, with gelling temperature of the nasal gel ranging between 33 and 34, respectively. The gel strength of the formulations varied from 4.67 and 0.68 mm and the drug content was 100%. The pH of the formulations ranged between 6.71 and 7.11. Detachment force was acceptable (63.69-244.16 N/cm2) to provide prolonged adhesion. In vitro, drug release studies showed that the prepared formulations could release SL for up to 8 h. Permeation flux for the S10 gel was 0.0002 mg/min/cm2. Results demonstrated that the potential use of SL gels can enhance the therapeutic effect of SL through the intranasal administration.

Effects of nanoadditives on the performance and emissions of rapeseed biodiesel in an insulated piston diesel engine.

Energy consumption and management have emerged as crucial production functions because of the high cost of energy. Since the total consumption of fossil fuels like diesel has increased proportionally to the expansion in demand for power generation, industry, and transportation services, researchers have long been interested in constructing a more energy-efficient engine. With its improved efficiency, reduced fuel consumption, and fewer emissions, the application of nano-coating technology to engine components has become more popular in recent years. This study involved the application of a thermal barrier coating (TBC) using zirconia on the test engine piston. The aim of this research is to examine the impact of aluminium oxide nano-additives in rapeseed biodiesel blends on the performance of a diesel engine with a thermal barrier-coated piston. The four test fuels were prepared using 20% and 40% blends of rapeseed biodiesel with and without the addition of aluminium oxide at 25 ppm and 50 ppm. The full factorial design methodology was employed to examine the influential factors, specifically the rapeseed blend ratio and aluminium oxide concentration, in order to enhance performance and reduce emissions. The blends of RSB20AO25 and RSB20AO50 showed significant results on energy consumption and emissions. The RSB20AO50 blend performed with a 5.4% increase in brake thermal efficiency and a 6.5% reduction in fuel consumption compared with standard diesel. Similarly, blends of RSB20AO25 and RSB20AO50 show 6% and 11% reductions in carbon monoxide and 5.2% and 9.5% reductions in hydrocarbon emissions.

Third wave of COVID-19: mathematical model with optimal control strategy for reducing the disease burden in Nigeria.

The study of COVID-19 pandemic which paralyzed global economy of countries is a crucial research area for effective future planning against other epidemics. Unfortunately, we now have variants of the disease resulting to what is now known as waves of the pandemic. Several mathematical models have been developed to study this disease. While recent models incorporated control measures, others are without optimal control measures or demographic parameters. In this study, we propose a deterministic compartmental epidemiological model to study the transmission dynamic of the spread of the third wave of the pandemic in Nigeria, and we incorporated optimal control measures as strategies to reduce the burden of the deadly disease. Specifically, we investigated the transmission dynamics of COVID-19 model without demographic features. We then conducted theoretical analysis of the model with and without optimal control strategy. In the model without optimal control, we computed the reproduction number, an epidemiological threshold useful for bringing the third wave of the pandemic under check in Nigeria, and we proofed the disease stability and conducted sensitivity analysis in order to identify parameters that can impact the reproduction number tremendously. In a similar reasoning, for the model with control strategy, we check the necessary condition for the model. To validate our theoretical analyses, we illustrated the applications of the proposed model using COVID-19 data for Nigeria for a period when the country was under the yoke of the third wave of the disease. The data were then fitted to the model, and we derived a predictive tool toward making a forecast for the cumulative number of cases of infection, cumulative number of active cases and the peak of the third wave of the pandemic. From the simulations, it was observed that the presence of optimal control parameters leads to significant impact on the reduction of the spread of the disease. However, it was discovered that the success of the control of the disease relies on the proper and effective implementation of the optimal control strategies efficiently and adequately.

Development, Statistical Optimization and Characterization of Fluvastatin Loaded Solid Lipid Nanoparticles: A 32 Factorial Design Approach.

The purpose of the present research work was to design, optimize, and evaluate fluvastatin-loaded solid lipid nanoparticles (FLV-SLNPs) using 32 factorial design for enhancing the bioavailability. Fluvastatin has several disadvantages, including the low solubility and substantial first-pass metabolism resulting in a low (30%) bioavailability and a short elimination half-life. FLV-SLNPs were prepared using the nano-emulsion technique. For the optimization of the FLV-SLNPs, a total of nine formulations were prepared by varying two independent factors at three levels, using full factorial design. In this design, lipid (A) and surfactant (B) concentrations were chosen as independent factors, whereas entrapment efficiency (Y1) and in-vitro drug release (Y2) were selected as the dependent variables. Additionally, the prepared SLNPs were characterized for X-ray diffraction, Fourier transform-infrared spectroscopy, and differential scanning calorimetry. These studies revealed that there were no interactions between the drug and the selected excipients and the selected formulation components are compatible with the drug. Pharmacokinetic studies in rats confirmed significant improvement in AUC and MRT of SLNPs in comparison with the pure drug indicating the enhanced bioavailability of SLNPs. This study provides a proof-of-concept for the fact that SLNPs can be effectively developed via experimental factorial design, which requires relatively minimal experimentation.

D-optimal mixture design for optimization of topical dapsone niosomes: in vitro characterization and in vivo activity against Cutibacterium acnes.

This study aimed to illustrate the use of D-optimal mixture design (DOMD) for optimization of an enhancer containing Dapsone niosomal formula for acne topical treatment. Mixture components (MixCs) studied were: Span 20, Cholesterol, and Cremophor RH. Different responses were measured. Optimized formula (OF) was selected to minimize particle size and maximize absolute zeta potential and entrapment efficiency. Optimized formula gel (OF-gel) was prepared and characterized. OF-gel in vivo skin penetration using confocal laser scanning microscopy and activity against Cutibacterium acnes in acne mouse model were studied. Based on DOMD results analysis, adequate models were derived. Piepel and contour plots were plotted accordingly to explain how alteration in MixCs L-pseudo values affected studied responses and regions for different responses' values. The OF had suitable predicted responses which were in good correlation with the actually measured ones. The OF-gel showed suitable characterization and in vivo skin penetration up to the dermis layer. In vivo acne mouse-model showed that OF-gel-treated group (OF-gel-T-gp) had significantly better recovery (healing) criteria than untreated (UT-gp) and Aknemycin®-treated (A-T-gp) groups. This was evident in significantly higher reduction of inflammation percent observed in OF-gel-T-gp than both UT-gp and A-T-gp. Better healing in OF-gel-T-gp compared with other groups was also verified by histopathological examination. Moreover, OF-gel-T-gp and A-T-gp bacterial loads were non-significantly different from each other but significantly lower than UT-gp. Thus, DOMD was an adequate statistical tool for optimization of an appropriate enhancer containing Dapsone niosomal formula that proved to be promising for topical treatment of acne.

Statistical Sequential Experimentation: Preliminary Mixed Factorial Design, I-Optimal Mixture Design Then Finally Novel Design Space Expansion for Optimization of Tazarotene Cubosomes.

Objective: This study aims to illustrate the potential of sequential experimentation for statistically scientific based optimization of Tazarotene (TAZA) cubosomes. Methods: Hot melt emulsification method was used for cubosomes preparation. A preliminary (3.2) mixed factorial design (MFD) was conducted to choose suitable types of stabilizer and surfactant that maximize entrapment efficiency (EE) and minimize particle size (PS). These chosen stabilizer and surfactant were to be used in the statistical design proposed for optimization of TAZA cubosomes (I-optimal mixture design) (IOMD). Glyceryl monooleate (GMO), stabilizer and surfactant amounts were the three mixture components (MixCs) studied in that design. Responses (EE, PS and drug percent released after 24 hours (Q24h)) were statistically analyzed. Numerical optimization using desirability function based on different responses' importance was used to find an IOMD-optimized formulation (IOMD-OF) with the predetermined characters. Then, a novel statistical methodology of design space expansion was adopted to enhance Q24h. Suitable models to express EE, PS and Q24h were elucidated over the expanded mixture design (EMD) space. Validity of derived models was verified via prediction intervals and percent deviations of actual values from predicted ones for all the EMD design points. EMD was then navigated to find EMD-OF. Results: Analysis of MFD showed that Pluronic-F68 and polyvinyl alcohol were the best stabilizer and surfactant to be used. First stage optimization after IOMD analysis led to a formulation with unsatisfactory Q24h of 58.8%. After design space expansion adoption, re-analysis and re-optimization, a satisfactory EMD-OF having EE of 82.1%, PS of 273.0 nm and Q24h of 68.8% was found. Conclusion: Statistical sequential experimentation with the novel design space expansion approach proved to be a successful paradigm for enhancing TAZA cubosomes optimization. Thus, this paradigm is expected to have promising future applications in various pharmaceutical formulations optimization.

QSCR Analysis of Cytotoxicity of 6-Fluoro-3-(4H-1,2,4-triazol-3- yl)quinolin-4(1H)-ones on Chinese Hamster Ovary Cell Line: Design of REPUBLIC1986.

BACKGROUND: 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-ones are promising antitumor agents with enormous data on their profound cytotoxic effects on the human cancer cell lines. OBJECTIVES: We sought to perform a Quantitative structure cytotoxicity relationship (QSCR) analysis of a series of previously reported fluoroquinolone analogues using computerassisted multiple regression analysis and investigate the cytotoxicity-inducing structural parameters among these congeners. METHODS: The dataset was segregated into training and test sets of 6-Fluoro-3-(4H-1,2,4- triazol-3-yl)quinolin-4(1H)-ones by using a random selection method embedded in Vlife MDS 4.6 software and subjected to QSCR analysis. Next, cross-validation of the generated QSCR models was performed along with the external test set prediction. Finally, the data was analyzed and contour plots were developed to deduce the cytotoxicity-inducing structural parameters among these congeners using Minitab® software. RESULTS: The validated QSCR model exhibited a statistically significant predictive value of 92.27 percent. Our QSCR model revealed a direct proportionality between hydrogen counts and cytotoxicity, and exclusion of sulphur and nitrogen with lesser crowding of cyclopropyl rings in future potential 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-one analogues. Based on the QSCR model predictions and contour plot analysis, the de novo REPUBLIC1986 molecule provided the best hit with predicted IC50 (µM) of 0.45 against CHO cell line and is amenable to salt formation crucial for anti-ovarian cancer activity. CONCLUSION: These findings suggest the relevancy of the developed QSCR model in designing novel, potent, and safer anti-cancer drugs with 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin- 4(1H)-ones as seed compounds.

Determinants of zero-order release kinetics from acetaminophen-layered Suglet® pellets, Wurster-coated with plasticized Aquacoat® ECD (ethyl cellulose dispersion).

The potential for zero-order drug-release was evaluated for ethyl cellulose (EC) coated, acetaminophen-layered sugar pellets (Suglets®) of mesh size 18/20 (850-1000 µm). To determine optimal plasticizer/pore-former concentrations for EC films, solvent-cast Aquacoat® ECD (ethyl cellulose dispersion) films were prepared with 0-50% w/w ratios of two triethyl citrate (TEC) or triacetin (TA). Characterization studies showed that films with excipient concentrations ≥20% were homogenous, mechanically strong at room temperature (Young's modulus of 25-35 MPa), and have a glass transition (Tg) in the range of 20-45 °C. Based on these results, a working range of 20-50% weight concentrations was selected for drug release studies. Suglets® were layered with acetaminophen (APAP) using Wurster Glatt GPCG-3 to yield roughly 10% w/w coating (controls). The Controls were coated using the same Wurster process with Aquacoat® ECD containing 20-50% w/w of TEC or TA. Samples were removed periodically at 3-11% weight gain, to evaluate impact of weight gain, and consequently film-formation, on drug release. Dissolution was monitored over a period of 12 h in a media consisting of simulated gastric fluid (first two hours), followed by simulated intestinal fluid. The controls showed near 100% release within the first 30 min, indicating the value of EC-coating to achieve controlled release. Dissolution release profiles showed that TEC is more effective than TA as a plasticizer and pore-former, as linear profiles were apparent at lower concentrations and % weight gain. For a quantitative evaluation of these results, linear regression was fitted to all cumulative release profiles, and R-squared values examined as a function of excipient concentration and % weight gain. The corresponding response surface plots and the second order regression were shown to aid in optimization. The design space for zero-order release was represented as contour plots between excipient concentration and % weight gain.

Valorization of coal fired-fly ash for potential heavy metal removal from the single and multi-contaminated system.

In this study, adsorption of three different heavy metals i.e. cadmium (Cd (II)), copper (Cu (II)) and nickel (Ni (II)) was carried out in single and multi-contaminated system using coal-fired fly ash (CFFA). Initially, for the single contaminated system, various physical process parameters were selected for optimization by deploying Box-Behnken design of experiments. Further, the evaluation of CFFA for removal of heavy metals in a multi-component system from aqueous solution was performed by employing Plackett-Burman design of experiments with all the three heavy metals at two different levels by varying their initial concentration (10-50 mg L-1). In both the aforementioned cases, CFFA showed its great potential for heavy metal removal, i.e. single and multi-component system and followed the order: Cu (II) > Ni (II) > Cd (II). Further, FTIR study confirmed the involvement of amide, aldehyde, alkoxy, alkanes, and alkene groups for heavy metal adsorption by CFFA.

Modelling the sporulation of some fungi associated with cheese, at different temperature and water activity regimes.

The objectives of this study were to determine, in-vitro, the influence of temperature (T; 10-30 °C, step 5°), water activity (aw, 0.83-0.99; step 0.04) and time on sporulation (SPO) of some cheese-related fungi belonging to Penicillium spp. and A. versicolor. Overall, sporulation started rapidly (8 h in optimal conditions); it was significantly influenced by T and aw and the fungi studied were clearly distinguished based on their thermo-hydro adaptation. Boundary conditions for sporulation were defined for all the fungi considered and the sporulation rate was successfully modelled, especially based on T and time regimes. Penicillium crustosum, P. nordicum and P. verrucosum showed optimum for SPO at T between 20 and 25 °C and their sporulation continued up to aw = 0.87 (aw = 0.83 for P. nordicum). They resulted the fungi best adapted to the environmental conditions of ripening grana cheese storehouses; therefore, it is expected they dominate on the grana cheese surface. Studies on cheese are necessary to validate these results obtained on artificial media and without fungi co-occurrence.

Risk based approach for design and optimization of stomach specific delivery of rifampicin.

The research envisaged focuses on risk management approach for better recognizing the risks, ways to mitigate them and propose a control strategy for the development of rifampicin gastroretentive tablets. Risk assessment using failure mode and effects analysis (FMEA) was done to depict the effects of specific failure modes related to respective formulation/process variable. A Box-Behnken design was used to investigate the effect of amount of sodium bicarbonate (X1), pore former HPMC (X2) and glyceryl behenate (X3) on percent drug release at 1st hour (Q1), 4th hour (Q4), 8th hour (Q8) and floating lag time (min). Main effects and interaction plots were generated to study effects of variables. Selection of the optimized formulation was done using desirability function and overlay contour plots. The optimized formulation exhibited Q1 of 20.9%, Q4 of 59.1%, Q8 of 94.8% and floating lag time of 4.0 min. Akaike information criteria and Model selection criteria revealed that the model was best described by Korsmeyer-Peppas power law. The residual plots demonstrated no existence of non-normality, skewness or outliers. The composite desirability for optimized formulation computed using equations and software were 0.84 and 0.86 respectively. FTIR, DSC and PXRD studies ruled out drug polymer interaction due to thermal treatment.

Improved antimicrobial compound production by a new isolate Streptomyces hygroscopicus MTCC 4003 using Plackett-Burman design and response Surface methodology.

An active strain, isolated from soil of Chhattisgarh, India, showed broad-spectrum antimicrobial activity against various pathogenic bacteria and fungi in glucose soybean meal broth. Strain was characterized as Streptomyces hygroscopicus MTCC 4003 based on 16S rRNA sequencing from Microbial Type culture Collection (MTCC), IMTECH, Chandigarh, India. Identification of the purified antimicrobial compound was done by using Infra-red (IR), Mass, Ultraviolet (UV), 1H and 13C nuclear magnetic resonance (NMR) spectra. Plackett-Burman design (PBD) and response surface methodology (RSM) methods were used for the optimization of antibiotic production. Effects of the four medium components soybean meal, glucose, CaCO3 and MgSO4 showed positive effect on antibiotic production, were investigated with the help of PBD. The individual and interaction effects of the selected variables were determined by RSM using central composite design (CCD). Applying statistical design, antibiotic production was improved nearly ten times (412 mg/L) compared with unoptimized production medium (37 mg/L).

Developing micro-/nanoparticulate drug delivery systems using "design of experiments".

Of late, micro and nanoparticluate drug delivery systems have been gaining immense importance primarily attributed to their improved drug release controlling and targeting efficiencies. Also, the small particle size and desirable surface charge associated with these delivery systems render them suitable for specific applications like lymphatic uptake, pulmonary uptake, tumor targeting, brain targeting, etc. For decades, micro and nanoparticulate systems have been prepared by the conventional "trial and error" approach of changing One Variable at a Time (OVAT). Using this methodology, the solution of a specific problematic formulation characteristic can certainly be achieved, but attainment of the true optimal composition is never guaranteed. Thus, the present manuscript provides an updated account of the systematic approach "Design of Experiments (DoE)" as applicable to formulation development of microparticles and nanostructured systems. Besides providing a bird's eye view of the various experimental designs and optimization techniques employed for DoE optimization of such systems, the present manuscript also presents a copilation of the major micro/nano-structuctred systems optimized through DoE till date. In a nutshell, the article will act both as a ready reckoner of DoE optimization of micro/nano drug delivery systems and a catalyst in providing an impetus to young pharmaceutical "nano & micro" researchers to venture into the rewarding field of systematic DoE optimization.