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This article reports on an experiment that studied the critical angular clamping speeds for fasteners using the Design of Experiments (DOE) methodology and Analysis of Variance (ANOVA). The study aimed to investigate the stick-slip phenomenon, a critical factor limiting the angular speed. The stick-slip was measured using the stick-slip factor, which is defined as the ratio of stick-slip chattering amplitude to frequency. The investigation focused on the factors that affect the stick-slip factor, torque, and clamping force (preload): friction coefficient, clamping angular velocity, cathodic electrodeposition, and hardness of the bolthead bearing plate. Automated predictive algorithms can utilize the data collected from this study to prevent the occurrence of the stick-slip phenomenon in screw clamping processes.

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In this work, a comparison was made between the synthesis of niobium-based materials (Nb2O5), both in terms of material characterization and catalytic performance. The methods used were chemical mixtures: modified sol-gel and Pechini. The materials were calcined at different temperatures (753, 873 and 993K) and characterized by the following techniques: photoacousticspectroscopy (PAS), zero charge point (pHPZC), scanning electron microscopy (SEM/EDS), thermogravimetric analysis (TGA/DTG) and X-ray diffraction (XRD). The photocatalytic process was carried out to evaluate the degradation of 2,4-dichlorophenoxyacetic acid (2,4-D) under UV radiation (250 W mercury vapor lamp) and different experimental conditions. In addition, to better understand the influence of parameters such as pH, catalyst concentration (0.2, 0.5 and 0.8 g L-1) and calcination temperature, a Design of Experiments (DoE) was used. The results indicated that despite having similar structures and phases in the XRD analysis, the morphology presents two distinct surfaces, due to the preparation method. Differences in the synthesis method affected the catalytic activity in the parameters studied. Although the zero charge point values are close (6.18-6.36), we observed differences in the band gap depending on the calcination temperature. In the optimal condition studied, the catalyst prepared by the sol-gel method obtained the best results.

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Plant-based materials are an important source of bioactive compounds (BC) with interesting industrial applications. Therefore, adequate experimental strategies for maximizing their recovery yield are required. Among all procedures for extracting BC (maceration, Soxhlet, hydro-distillation, pulsed-electric field, enzyme, microwave, high hydrostatic pressure, and supercritical fluids), the ultrasound-assisted extraction (UAE) highlighted as an advanced, cost-efficient, eco-friendly, and sustainable alternative for recovering BC (polyphenols, flavonoids, anthocyanins, and carotenoids) from plant sources with higher yields. However, the UAE efficiency is influenced by several factors, including operational variables and extraction process (frequency, amplitude, ultrasonic power, pulse cycle, type of solvent, extraction time, solvent-to-solid ratio, pH, particle size, and temperature) that exert an impact on the molecular structures of targeted molecules, leading to variations in their biological properties. In this context, a diverse design of experiments (DOEs), including full or fractional factorial, Plackett-Burman, Box-Behnken, Central composite, Taguchi, Mixture, D-optimal, and Doehlert have been investigated alone and in combination to optimize the UAE of BC from plant-based materials, using the response surface methodology and mathematical models in a simple or multi-factorial/multi-response approach. The present review summarizes the advantages and limitations of the most common DOEs investigated to optimize the UAE of bioactive compounds from plant-based materials.

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This study aimed to develop a biopredictive dissolution method for desvenlafaxine ER tablets using design of experiments (DoE) and physiologically based biopharmaceutics modeling (PBBM) to address the challenge of developing generic drug products by reducing the risk of product failure in pivotal bioequivalence studies. For this purpose, a PBBM was developed in GastroPlus® and combined with a Taguchi L9 design, to evaluate the impact of different drug products (Reference, Generic #1 and Generic #2) and dissolution test conditions on desvenlafaxine release. The influence of the superficial area/volume ratio (SA/V) of the tablets was observed, mainly for Generic #1, which presented higher SA/V than the others, and a high amount of drug dissolved under similar test conditions. The dissolution test conditions of 900 mL of 0.9% NaCl and paddle at 50 rpm with sinker showed to be biopredictive, as it was possible to demonstrate virtual bioequivalence for all products, despite their release-pattern differences, including Generic #3 as an external validation. This approach led to a rational development of a biopredictive dissolution method for desvenlafaxine ER tablets, providing knowledge that may help the process of drug product and dissolution method development.

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Diosgenin and its derivatives have proved a huge importance in diverse biological activities. The optimized production of the diastereoisomers of the epoxide of diosgenin acetate by means of mCPBA is reported herein. This transformation had a previous design of experiments using the application of a statistical factorial DoE of 4 parameters (nk), where one variable is varied at a time, while others stay constant. The temperature showed the greatest effect on the reaction yield; so, at 298 K the diastereomeric ratio 3:1 of α and ß-epoxides, normally found, was raised to 1:1. Time was the second significant variable, but due to its high correlation with temperature, 30 min were required for a global 90% conversion at least. These diastereoisomers were characterized both isolated and in the mixtures obtained, to determine their antioxidant, antimicrobial and antiproliferative activity, finding a low antioxidant capacity by DPPH, but antimicrobial activity at the level of penicillin in gram negative bacteria by 1ß better to 1α. The antiproliferative capacity was higher for diastereoisomer ß, agreeing with the proportion of the mixture obtained by different conditions, increasing this in relation to the amount of this diastereoisomer present in hormone-dependent cancer cell lines such as Hela, PC-3 and MCF-7, with 10.0 µM obtained values of viability at 21.8 %, 35.8 % and 12.3 % respectively. DoE optimization allows to manipulate the ratio between diastereoisomers with the minimum number of experiments, extending the analysis of the effect of the ratio between diastereoisomers and the in silico potential as well as the biological activity.

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Introduction: Cell membrane-covered biomimetic nanosystems have allowed the development of homologous nanostructures to bestow nanoparticles with enhanced biointerfacing capabilities. The stability of these structures, however, still represents a challenge for the scientific community. This study is aimed at developing and optimizing cell derived membrane-coated nanostructures upon applying design of experiments (DoE) to improve the therapeutic index by homotypic targeting in cancer cells. Methods: Important physicochemical features of the extracted cell membrane from tumoral cells were assessed by mass spectrometry-based proteomics. PLGA-based nanoparticles encapsulating temozolomide (TMZ NPs) were successfully developed. The coating technology applying the isolated U251 cell membrane (MB) was optimized using a fractional two-level three-factor factorial design. All the formulation runs were systematically characterized regarding their diameter, polydispersity index (PDI), and zeta potential (ZP). Experimental conditions generated by DoE were also subjected to morphological studies using negative-staining transmission electron microscopy (TEM). Its short-time stability was also assessed. MicroRaman and Fourier-Transform Infrared (FTIR) spectroscopies and Confocal microscopy were used as characterization techniques for evaluating the NP-MB nanostructures. Internalization studies were carried out to evaluate the homotypic targeting ability. Results and Discussion: The results have shown that nearly 80% of plasma membrane proteins were retained in the cell membrane vesicles after the isolation process, including key proteins to the homotypic binding. DoE analysis considering acquired TEM images reveals that condition run five should be the best-optimized procedure to produce the biomimetic cell-derived membrane-coated nanostructure (NP-MB). Storage stability for at least two weeks of the biomimetic system is expected once the original characteristics of diameter, PDI, and ZP, were maintained. Raman, FTIR, and confocal characterization results have shown the successful encapsulation of TMZ drug and provided evidence of the effective coating applying the MB. Cell internalization studies corroborate the proteomic data indicating that the optimized NP-MB achieved specific targeting of homotypic tumor cells. The structure should retain the complex biological functions of U251 natural cell membranes while exhibiting physicochemical properties suitable for effective homotypic recognition. Conclusion: Together, these findings provide coverage and a deeper understanding regarding the dynamics around extracted cell membrane and polymeric nanostructures interactions and an in-depth insight into the cell membrane coating technology and the development of optimized biomimetic and bioinspired nanostructured systems.

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Assessing volatile organic compounds (VOCs) as cancer signatures is one of the most promising techniques toward developing non-invasive, simple, and affordable diagnosis. Here, we have evaluated the feasibility of employing static headspace extraction (HS) followed by gas chromatography with flame ionization detector (GC-FID) as a screening tool to discriminate between cancer patients (head and neck-HNC,n= 15; and gastrointestinal cancer-GIC,n= 19) and healthy controls (n= 37) on the basis of a non-target (fingerprinting) analysis of oral fluid and urine. We evaluated the discrimination considering a single bodily fluid and adopting the hybrid approach, in which the oral fluid and urinary VOCs profiles were combined through data fusion. We used supervised orthogonal partial least squares discriminant analysis for classification, and we assessed the prediction power of the models by analyzing the values of goodness of prediction (Q2Y), area under the curve (AUC), sensitivity, and specificity. The individual models HNC urine, HNC oral fluid, and GIC oral fluid successfully discriminated between healthy controls and positive samples (Q2Y = 0.560, 0.525, and 0.559; AUC = 0.814, 0.850, and 0.926; sensitivity = 84.8, 70.2, and 78.6%; and specificity = 82.3; 81.5; 87.5%, respectively), whereas GIC urine was not adequate (Q2Y = 0.292, AUC = 0.694, sensitivity = 66.1%, and specificity = 77.0%). Compared to the respective individual models, Q2Y for the hybrid models increased (0.623 for hybrid HNC and 0.562 for hybrid GIC). However, sensitivity was higher for HNC urine and GIC oral fluid than for hybrid HNC (75.6%) and hybrid GIC (69.8%), respectively. These results suggested that HS-GC-FID fingerprinting is suitable and holds great potential for cancer screening. Additionally, the hybrid approach tends to increase the predictive power if the individual models present suitable quality parameter values. Otherwise, it is more advantageous to use a single body fluid for analysis.

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The present work proposes the optimization of enzymatic synthesis of alkyl stearates using stearic acid, alkyl alcohols (C1-OH, C2-OH, C4-OH, C8-OH and C16-OH) and Candida rugosa lipase by a L9 (34) Taguchi-type design of experiments. Four variables were evaluated (reaction time, temperature, kU of lipase and alcohol:stearic acid molar ratio), ensuring that all variables were critical. In optimal conditions, five stearates were obtained with conversions > 90%. The obtained products were characterized by nuclear magnetic resonance (NMR). Additionally, the defoaming capacity of the five stearates was evaluated, obtaining better performance for the compound synthesized from C8-OH alcohol.

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Serology assays are essential tools to mitigate the effect of COVID-19, help to identify previous SARS-CoV-2 infections or vaccination, and provide data for surveillance and epidemiologic studies. In this study, we report the production and purification process of the receptor-binding domain (RBD) of SARS-CoV-2 in HEK293 cells, which allowed the design, optimization, and validation of an indirect ELISA (iELISA) for the detection of human anti-RBD antibodies. To find the optimal conditions of this iELISA, a multivariate strategy was performed throughout design of experiments (DoE) and response surface methodology (RSM), one of the main tools of quality by design (QbD) approach. The adoption of this strategy helped to reduce the time and cost during the method development stage and to define an optimum condition within the analyzed design region. The assay was then validated, exhibiting a sensitivity of 94.24 (86.01-98.42%; 95% CI) and a specificity of 95.96% (89.98-98.89%; 95% CI). Besides, the degree of agreement between quality results assessed using kappa's value was 0.92. Hence, this iELISA represents a high-throughput technique, simple to perform, reliable, and feasible to be scaled up to satisfy the current demands. Since RBD is proposed as the coating antigen, the intended use of this iELISA is not only the detection of previous exposure to the virus, but also the possibility of detecting protective immunity. KEY POINTS: • RBD was produced in 1-L bioreactor and highly purified. • An iELISA assay was optimized applying QbD concepts. • The validation procedure demonstrated that this iELISA is accurate and precise.

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INTRODUCTION: Medical uses of Cannabis sativa L. have gained interest in recent decades, which highlights the need for defining appropriate quality specifications for Cannabis-based products. However, the complexity of plant matrices and structural similarity between cannabinoids make analytical development a challenging task. Thus, the application of analytical quality by design (AQbD)-driven approaches can favour the development of fit-for-purpose methods. OBJECTIVES: To develop a high-performance liquid chromatography diode array detector (HPLC-DAD) method for simultaneous quantification of cannabidiol, Δ9 -tetrahydrocannabinol, cannabidiolic acid, tetrahydrocannabinolic acid, and cannabinol in C. sativa by applying an AQbD-driven approach. MATERIALS AND METHODS: Critical method attributes (CMA) were established following the analytical target profile. Critical method variables (CMV) were categorised based on risk assessment and literature review. Selected CMV regarding sample preparation and chromatographic conditions were optimised using response surface methodology (RSM). The working point was estimated by multiple response optimisation using Deringer's desirability function. The validity of the optimal conditions was confirmed experimentally. Method validation was performed according to ANVISA and ICH guidelines. Relative response factors (RRFs) were also determined. RESULTS AND DISCUSSION: Baseline resolution of 12 major cannabinoids was achieved in a 35 min chromatographic analysis. All experimental responses obtained during confirmatory analyses were within the prediction intervals (PI95% ). Method's selectivity, linearity (10-100 µg/mL), precision, bias, extraction recovery, and ruggedness were satisfactorily demonstrated. CONCLUSIONS: The application of an AQbD-driven approach allowed for a better understanding of the effects of the ensemble of CMV on the analyte's behaviour, enabling the definition of appropriate conditions to ensure consistent achievement of the intended method's performance.

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Halophilic microorganisms are potentially capable as platforms to produce low-cost biosurfactants. However, the robustness of bioprocesses is still a challenge and, therefore, it is essential to understand the effects of microbiological culture conditions through bioreactor engineering. Based on a design of experiments (DOE) and a response surface methodology (RSM) tailored and taken from the literature, the present work focuses on the evaluation of a composite central design (CCD) under batch cultures in stirred-tank bioreactors with the halophilic bacteria Salibacterium sp. 4CTb in order to determine the operative conditions that favor mass transfer and optimize the production of a lipopeptide. The results obtained showed profiles highlighting the most favorable culture conditions, which lead to an emulsification index (E24%) higher than 70%. Moreover, through the behavior of dissolved oxygen (DO), it was possible to experimentally evaluate the higher volumetric coefficient of mass transfer in the presence of lipopeptide (kLa = 31 1/h) as a key criterion for the synthesis of the biosurfactant on further cell expansion.

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The development of extended-release dosage forms with adequate drug release is a challenge for pharmaceutical companies, mainly when the drug presents high solubility, as in Biopharmaceutics Classification System (BCS) class I. This study aimed to develop extended-release mini-tablets containing metoprolol succinate (MS), while integrating design of experiments (DOE) and physiologically based biopharmaceutics modeling (PBBM), to predict its absorption and to run virtual bioequivalence (VBE) studies in both fasted and fed states. Core mini-tablet formulations (F1, F2, and F3) were prepared by direct compression and coated using nine coating formulations planned using DOE, while varying the percentages of the controlled-release and the pore-forming polymers. The coated mini-tablets were submitted to a dissolution test; additional formulations were prepared that were optimized by simulating the dissolution profiles, and the best one was submitted to VBE studies using GastroPlus® software. An optimized formulation (FO) containing a mixture of immediate and extended-release mini-tablets showed to be bioequivalent to the reference drug product containing MS when running VBE studies in both fasted and fed states. The integration of DOE and PBBM showed to be an interesting approach in the development of extended-release mini-tablet formulation containing MS, and can be used to rationalize the development of dosage forms.

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Today, a growing number of computational aids and simulations are shaping model-informed drug development. Artificial intelligence, a family of self-learning algorithms, is only the latest emerging trend applied by academic researchers and the pharmaceutical industry. Nanomedicine successfully conquered several niche markets and offers a wide variety of innovative drug delivery strategies. Still, only a small number of patients benefit from these advanced treatments, and the number of data sources is very limited. As a consequence, "big data" approaches are not always feasible and smart combinations of human and artificial intelligence define the research landscape. These methodologies will potentially transform the future of nanomedicine and define new challenges and limitations of machine learning in their development. In our review, we present an overview of modeling and artificial intelligence applications in the development and manufacture of nanomedicines. Also, we elucidate the role of each method as a facilitator of breakthroughs and highlight important limitations.

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Fungal secondary metabolites with antimicrobial properties are used for biological pest control. Their production is influenced by several factors as environment, host, and culture conditions. In the present work, the secondary metabolites from fermented extracts of Beauveria bassiana PQ2 were tested as antifungal agents against Gibberella moniliformis LIA. The L18 (21 × 37) orthogonal array from Taguchi methodology was used to assess 8 parameters (pH, agitation, sucrose, yeast extract, KH2PO4, MgSO4, NH4NO3, and CaCl2) in B. bassiana PQ2 submerged fermentation. The ability of the fermented extracts to slow down the growth rate of G. moniliformis LIA was evaluated. The results from 18 trials were analyzed by Statistica 7 software by evaluating the signal-to-noise ratio (S/N) to find the lower-the-better condition. Optimal culture conditions were pH, 5; agitation, 250 rpm; sucrose, 37.5 g/L-1; yeast extract, 10 g/L-1; KH2PO4, 0.8 g/L-1; MgSO4, 1.2 g/L-1; NH4NO3, 0.1 g/L-1; and CaCl2, 0.4 g/L-1, being the agitation at the highest level the most significant factor. The optimal conditions were validated in a sparged bottle bioreactor resulting in a higher S/N value (12.48) compared to the estimate. The extract obtained has the capacity to inhibit the germination of G. moniliformis spores at 24 h. HPLC-ESI-MS2 allowed to identify the water-soluble red pigment as oosporein (m/z 304.9). The secondary metabolites from B. bassiana PQ2 are a suitable alternative to control the growth and sporulation of G. moniliformis.

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Design of Experiments (DoE) is a statistical tool used to plan and optimize experiments and is seen as a quality technology to achieve products excellence. Among the experimental designs (EDs), the mixture designs (MDs) stand out, being widely applied to improve conditions for processing, developing, or formulating novel products. This review aims to provide useful updated information on the capacity and diversity of MDs applications for the industry and scientific community in the areas of food, beverage, and pharmaceutical health. Recent works were selected following the Preferred Reporting Items for Systematic Review and Meta-Analyses statement (PRISMA) flow diagram. Data analysis was performed by self-organizing map (SOM) to check and understand which fields of application/countries/continents are using MDs. Overall, the SOM indicated that Brazil presented the largest number of works using MDs. Among the continents, America and Asia showed a predominance in applications with the same amount of work. Comparing the MDs application areas, the analysis indicated that works are prevalent in food and beverage science in the American continent, while in Asia, health science prevails. MDs were more used to develop functional/nutraceutical products and the formulation of drugs for several diseases. However, we briefly describe some promising research fields in that MDs can still be employed.

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The global feed conversion is a variable used to measure feed efficiency in production systems. The number of rabbits produced/doe/year is the most influential factor on production cost. Feeding can be considered a variable cost in livestock, because it varies with the number of rabbits, and that cost becomes diluted when the number of rabbits produced increases. The aim of the present work was to analyze factors that influenced the global feed conversion ratio (FCR) of a semi-intensive rabbit production system of Azul, Buenos Aires province, Argentina. Five breeds (Californian, New Zealand White, New Zealand Black, Butterfly, and Fauve de Bourgogne) were used. The doe productivity varied according to the applied reproduction rhythm (p=0.002), being an average of 1.29±0.09 animal produced/doe/month for the rhythm of 52 days, and 2.38±0.28 for the rhythm of 42 days. The fertility rate was on the average 65% and 77% for the reproductive rhythm of 52 to 42 days respectively. A total of 20,091 kg of feed was required to produce 1027 rabbits (19.6 kg/animal), with a global feed conversion rate of 6.9. The slaughter weight varied according to the applied reproduction rhythm (p=0.008), with an average of 2.79±0.10 kg. However, in the first period, rabbits were heavier (3.31±0.15 kg). The rabbit/feed price ratio was 12.8 to 16 depending on the sale price (retail or wholesale), respectively. The doe productivity was different according the reproductive rhythm applied, and this affected the FCR and the feed consumed/rabbit produced.

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Navicula incerta is a marine microalga distributed in Baja California, México, commonly used in aquaculture nutrition, and has been extended to human food, biomedical, and pharmaceutical industries due to its high biological activity. Therefore, the study aimed to optimize culture conditions to produce antioxidant pigments. A central composite experimental design and response surface methodology (RSM) was employed to analyze the best culture conditions. The medium (nitrogen-deficient concentrations), salinity (PSU = Practical Salinity Unity [g/kg]), age of culture (days), and solvent extraction (ethanol, methanol, and acetone) were the factors used for the experiment. Chlorophyll a (Chl a) and total carotenoids (T-Car), determined spectroscopically, were used as the response variables. The antioxidant capacity was evaluated by DPPH• and ABTS•+ radical inhibition, FRAP, and anti-hemolytic activity. According to the overlay plots, the optimum growth conditions for Chl a and T-Car production were the following conditions: medium = 0.44 mol·L-1 of NaNO3, salinity = 40 PSU, age of culture: 3.5 days, and solvent = methanol. The pigment extracts obtained in these optimized conditions had high antioxidant activity in ABTS•+ (86.2-92.1% of inhibition) and anti-hemolytic activity (81.8-96.7% of hemolysis inhibition). Low inhibition (33-35%) was observed in DPPH•. The highest value of FRAP (766.03 ± 16.62 µmol TE/g) was observed in the acetonic extract. The results demonstrated that RSM could obtain an extract with high antioxidant capacity with potential applications in the biomedical and pharmaceutical industry, which encourages the use of natural resources for chemoprevention of chronic-degenerative pathologies.

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We developed a fast, rabies virus-free, in vitro method, based on a blocking ELISA (bELISA), to detect and accurately quantify anti-rabies glycoprotein antibodies in serum of several animal species. In this method, purified rabies virus-like particles (VLPs) are used as antigen to coat the plates, while the presence of specific rabies immunoglobulins is revealed through blocking the recognition of these VLPs by a biotinylated monoclonal antibody. A quality by design approach was carried out in order to optimize the method performance, improving the sensitivity and, thereby, reducing the limit of detection of this assay. After the method validation, we confirmed that the bELISA method is able to detect a concentration of 0.06 IU/mL rabies immunoglobulins, titer lower than the 0.5 IU/mL cutoff value established as indication for correct vaccination. Further, we assessed the correlation between bELISA, the MNT, and the Platelia methods, confirming the accuracy of this new assay. On the other hand, precision was evaluated, obtaining acceptable repeatability and intermediate precision values, showing that this bELISA could be proposed as a potential alternative method, replacing the gold standard techniques in vaccination schemes and becoming a routine control technique within regional rabies surveillance programs.

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The aim of the present work was the development of an innovative in situ gelling system, to be applied on the mucosa of the distal colon via rectal route. The system consisted of three polymers having different functions: gellan (GG), able to jellify in presence of ions; methylcellulose (MC), a thermosensitive polymer with a gelation temperature close to 50 °C; and hydroxypropylcellulose (HPC), a mucoadhesive polymer. The three polymers were able to act synergistically, increasing the permanence of the vehicle on the mucosa and forming a protective gel layer. A DoE approach, "simplex centroid mixture design," was used to identify the optimal quantitative composition of the vehicle. The response variables considered were: vehicle viscosity at room temperature; increase in vehicle viscosity on increasing temperature (from room to physiological value) and upon dilution with simulated colonic fluid (SCF); and viscoelastic behavior, thixotropic area, and mucoadhesion properties of the gel formed at 37 °C upon dilution in SCF. The optimized vehicle was loaded with maqui berry extract (MBE), known for its antioxidant and anti-inflammatory properties. MBE loading (0.5% w/w) into the vehicle improved rheological and mucoadhesive properties of the formulation. Both MBE and the optimized vehicle were not cytotoxic towards human fibroblasts and Caco-2 cells. Moreover, the optimized vehicle did not affect MBE antioxidant properties.

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In the present experiment, we tested the hypothesis that in does kidding in summer, melatonin administration during dry period is galactopoietic for the subsequent lactation and results in improved growth of their suckling kids. Twenty-five multiparous pregnant creole does were enrolled into a randomized complete block design during their dry period in the 49 d prepartum, and under natural long photoperiods around the summer solstice, pregnant does either received 2 subcutaneous ear implants (18 mg) of melatonin (MEL, n = 10) or served as nonimplanted controls (CONT, n = 15). During the first 14 wk of subsequent lactation (suckling and milking periods), MEL does yielded more milk than CONT does. Throughout subsequent lactation, milk composition was not affected by treatment. In MEL does, peripheral triiodothyronine levels peaked at 2 wk of lactation, remaining higher than in CONT does. The mean daily weight gain was higher in MEL compared with CONT kids and was also higher in males than females, and for males, was positively correlated with milk yield. The current data support our hypothesis that melatonin during the prepartum period is galactopoietic in suckling does.

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