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OBJECTIVE: This work aims to present a Quality-by-Design (QbD) step-by-step methodology to formulate anti-ulcer and gastro-protective oral suspensions. METHODS: Sucralfate was used as a drug model. The Quality Target Product Profile was established early during preformulation. Viscosity, resuspendability, pH, and density were assessed through the screening of several suspension platforms based on different prototype compositions. A compatibility study between the active pharmaceutical ingredient and the excipients was performed by thermal analysis and infrared spectroscopy. An Ishikawa fishbone diagram and Failure Mode and Effect Analysis were employed to identify the Critical Material Attributes (CMAs), Critical Process Parameters (CPPs), and Critical Quality Attributes (CQAs). CMAs' and CPPs' impact on identified CQAs was further assessed through a 22 full factorial experimental design at normal conditions after manufacture and one month at super-accelerated stress conditions. Results: The lead prototype exhibited no physicochemical incompatibilities. The risk assessment tools revealed that the concentration of the wetting agent and the total concentration of thickening agents represented critical factors for the quality profile of the preparation in terms of viscosity. The optimized formulation comprising 1.125 w/v% total concentration of Natrosol 250 HX and Avicel RC 591 exhibited an enhanced performance according to the established profile. CONCLUSIONS: The analytical and physicochemical tests showed the robustness and compliance of the final preparation with the quality profile. The proposed step-by-step methodology based on QbD, Design of Experiments, and Quality Risk Management presented in our research holds practical implications for local industries and formulation scientists involved in the development of oral suspensions.

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Almond trees are the most cultivated nut tree in the world. The production of almonds generates large amounts of by-products, much of which goes unused. Herein, this study aimed to develop a green chemistry approach to identify and extract potentially valuable compounds from almond by-products. Initially, a screening was performed with 10 different Natural Deep Eutectic Solvents (NADESs). The mixture lactic acid/glycerol, with a molar ratio 1:1 (1:50 plant material to NADES (w/v) with 20% v/v of water) was identified as the best extraction solvent for catechin, caffeoylquinic acid, and condensed tannins in almond hulls. Subsequently, a method was optimized by a Design of Experiment (DoE) protocol using a miniaturized extraction technique, Microwave-Assisted Extraction (MAE), in conjunction with the chosen NADESs. The optimal conditions were found to be 70 °C with 15 min irradiation time. The optimal extraction conditions determined by the DoE were confirmed experimentally and compared to methods already established in the literature. With these conditions, the extraction of metabolites was 2.4 times higher, according to the increase in total peak area, than the established literature methods used. Additionally, by applying the multiparameter Analytical Greenness Metric (AGREE) and Green Analytical Process Index (GAPI) metrics, it was possible to conclude that the developed method was greener than the established literature methods as it includes various principles of green analytical chemistry.

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The difficulty in swallowing is a frequent problem when oral solid dosage forms (conventional tablets or capsules) are administered to paediatric population or patients with dysphagia. An interesting alternative to overcome these problems are non-conventional formulations like chewable gels, commonly known as 'gummies'. Therefore, this work addresses the design, development and characterization of gummies using gelatine and pectin, for the vehiculization of the antiarrhythmic amiodarone (AMIO). Applying a Design of Experiments (DoE) approach, four gelatine (GG1-GG4) and eight pectin formulations (PG1-PG8) were developed. Considering the obtained results for responses during DoE evaluation (i.e., volume, syneresis, hardness, and gumminess), GG3 and PG8 were selected for complete characterization. Water activity, pH, drug content, texture parameters (adhesiveness, springiness, cohesiveness, and fracturability), disintegration time, in vitro dissolution, and microbiological features were evaluated. The obtained results were within the expected values for this type of formulation. The dissolution profiles showed a 94 % - 99 % of the AMIO content released for GG3 and PG8, respectively, so they could be considered suitable as immediate release dosage forms. In conclusion, the chewable gels were successfully developed and characterised, suggesting a potential means to accomplish a final prototype for the improvement of congenital cardiopathies treatment.

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The pecan nutshell [Carya illinoinensis (Wangenh) C. Koch] (PNS) is a source of bioactives with important beneficial properties for the human health. PNS represents between 40-50 % of total mass of the nut, resulting as waste without any added value for the food industry. Even though a variety of methods were already developed for bioactive extraction from this waste, unconventional methodologies, or those which apart from green chemistry principles, were discarded considering the cost of production, the sustainable development goals of United Nations and the feasibility of real inclusion of the technology in the food chain. Then, to add-value to this waste, a low-cost, green and easy-scalable extraction methodology was developed based on the determination of seven relevant factors by means of a factorial design and a Response Surface Methodology, allowing the extraction of bioactives with antioxidant capacity. The pecan nutshell extract had a high concentration of phenolic compounds (166 mg gallic acid equivalents-GAE/g dry weight-dw), flavonoids (90 mg catechin equivalent-CE/g dw) and condensed tannins (189 mg CE/g dw) -related also to the polymeric color (74.6 %)-, with high antioxidant capacities of ABTS+. radical inhibition (3665 µmol Trolox Equivalent-TE/g dw) and of iron reduction (1305 µmol TE/g dw). Several compounds associated with these determinations were identified by HPLC-ESI-MS/MS, such as [Epi]catechin-[Epi]catechin-[Epi]gallocatechin, myricetin, dihydroquercetins, dimers A and B of protoanthocyanidins, ellagitannins and ellagic acid derivatives. Hence, through the methodology developed here, we obtained a phenolic rich extract with possible benefits for human health, and of high industrial scalability for this co-product transformation.

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Microalgal biomass (MB) is a promising feedstock for bioenergy production. Nonetheless, the cell recalcitrance and the low C/N ratio limit the methane yield during anaerobic digestion. As an alternative to overcome these challenges, MB co-digestion with different feedstocks has been proposed. Thus, this study evaluated the anaerobic co-digestion (AcoD) of MB cultivated in wastewater with sugarcane vinasse (VIN) and residual glycerol from biodiesel production (GLY). Batch tests were conducted using augmented simplex-centroid mixture design to investigate the impact of AcoD on methane production (SMP), synergistic effects, and the influence on microbial community. When compared to MB digestion, 150 NmL CH4.g-1VS, binary and ternary AcoD achieved SMP increases from 120 to 337%. The combination of 16.7:16.7:66.7 (MB:VIN:GLY) showed the highest SMP for a ternary mixture (631 NmL CH4.g-1VS). Optimal synergies ranged from 1.3 to 1.4 and were primarily found for the MB:GLY AcoD. Acetoclastic Methanosaeta genus was predominant, regardless the combination between substrates. Despite the largest SMP obtained from the MB:GLY AcoD, other ternary mixtures were also highly synergetic and therefore had strong potential as a strategic renewable energy source.

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BACKGROUND: Important evidence has been constantly produced and needs to be converted into practice. Professional consumption of such evidence may be a barrier to its implementation. Then, effective implementation of evidence-based interventions in clinical practice leans on the understanding of how professionals value attributes when choosing between options for dental care, permitting to guide this implementation process by maximizing strengthens and minimizing barriers related to that. METHODS: This is part of a broader project investigating the potential of incorporating scientific evidence into clinical practice and public policy recommendations and guidelines, identifying strengths and barriers in such an implementation process. The present research protocol comprises a Discrete Choice Experiment (DCE) from the Brazilian oral health professionals' perspective, aiming to assess how different factors are associated with professional decision-making in dental care, including the role of scientific evidence. Different choice sets will be developed, either focusing on understanding the role of scientific evidence in the professional decision-making process or on understanding specific attributes associated with different interventions recently tested in randomized clinical trials and available as newly produced scientific evidence to be used in clinical practice. DISCUSSION: Translating research into practice usually requires time and effort. Shortening this process may be useful for faster incorporation into clinical practice and beneficial to the population. Understanding the context and professionals' decision-making preferences is crucial to designing more effective implementation and/or educational initiatives. Ultimately, we expect to design an efficient implementation strategy that overcomes threats and potential opportunities identified during the DCEs, creating a customized structure for dental professionals. TRIAL REGISTRATION: https://osf.io/bhncv .

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The inclusion of protein in the regular human diet is important for the prevention of several chronic diseases. In the search for novel alternative protein sources, plant-based proteins are widely explored from a sustainable and ecological point of view. Duckweed (Lemna minor), also known as water lentil, is an aquatic plant with potential applications for human consumption due to its protein content and carbohydrate contents. Among all the conventional and novel protein extraction methods, the utilization of ultrasound has attracted the attention of scientists because of its effects on improving protein extraction and its functionalities. In this work, a Box-Behnken experimental design was proposed to optimize the alkaline extraction of protein from duckweed. In addition, an exploration of the effects of ultrasound on the morphological, structural, and functional properties of the extracted protein was also addressed. The optimal extraction parameters were a pH of 11.5 and an ultrasound amplitude and processing time of 60% and 20 min, respectively. These process conditions doubled the protein content extracted in comparison to the value from the initial duckweed sample. Furthermore, the application of ultrasound during the extraction of protein generated changes in the FTIR spectra, color, and structure of the duckweed protein, which resulted in improvements in its solubility, emulsifying properties, and foaming capacity.

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MAIN CONCLUSION: Open-Top Chambers should be more used in tropical ecosystems to study climate change effects in plants as they are still insufficient to extract plant response patterns in these ecosystems. Understanding flora response to climate change (CC) is critical for predicting future ecosystem dynamics. Open-Top Chambers (OTCs) have been widely used to study the effects of CC on plants and are very popular in temperate ecosystems but are still underused in tropical regions. In this systematic review, we aimed to discuss the use of OTCs in the study of the effects of different agents of climate change on tropical flora by presenting scientometric data, discussing the technical aspects of its use and enumerating some observations on plant response patterns to climatic alterations in the tropics. Our analysis indicated that the bottleneck in choosing an OTC shape is not strictly related to its purpose or the type of parameter modulated; instead, passive or active approaches seem to be a more sensitive point. The common critical point in using this technique in warmer regions is overheating and decoupling, but it can be overcome with simple adaptations and extra features. The most frequently parameter modulated was CO2, followed by O3 and temperature. The plant families with more representatives in the studies analyzed were Fabaceae, Myrtaceae, and Poaceae, and the most represented biome was tropical and subtropical moist broadleaf forests. In conclusion, OTCs are a valuable and feasible tool to study CC effects on various tropical ecosystems, regardless of structure, active/passive approach, or other technical features. One of the primary advantages of this methodology is its applicability for in situ use, eliminating the need for plant transplantation. We encourage studies using OTC experimental design for plant conservation in the tropics.

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This paper analyses the impact of a healthy food nudge intervention on purchases of 1590 customers of a supermarket chain's loyalty program in Uruguay through a randomized controlled trial. Nudges were presented in the form of messages sent through WhatsApp to customers three times a week for 8 weeks (between July and September 2020). Messages highlighted the benefits of cooking at home and eating mindfully and healthy (vegetables, fruits, healthy snacks, legumes, and fish), and included easy to implement tips. Results show that, on average, customers assigned to the treatment group increased their purchases of healthy food by 8% and substituted sugar-sweetened for sugar-free beverages. We find an unintended increase in purchases of unhealthy food of 7%, with no correlative increase in calories, suggesting that customers substituted higher calorie products for lower calorie ones. We find that households with lower educational attainment, lower income, and with children under the age of 12 are more likely to increase purchases of fruits and vegetables, while other households are more likely to improve the diet quality without increasing expenditure. Effects do not persist after the intervention is over, suggesting that salience, rather than information is the main channel triggering the effects.

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Anthropogenic noise is a major global pollutant but its effects on primates are poorly understood, limiting our ability to develop mitigation actions that favor their welfare and conservation. In this study, we used an experimental approach to determine the impact of variation in noise intensity on mantled howler monkeys (Alouatta palliata). We conducted the study at Los Tuxtlas (México), where we studied the physiological stress (proxied via fecal glucocorticoid metabolites, fGCM) and behavioral responses of 16 males. We played back chainsaw noise at two intensities (40 and 80 dB) and used days in which groups were not exposed to noise as matched controls. With increased noise intensity fGCM increased, vigilance and vocalizations were longer, and vigilance, vocalizations, and flight occurred quicker. Physiological and behavioral responses occurred even after low-intensity noise playbacks (i.e., 40 dB). Therefore, noise intensity is a significant factor explaining the responses of mantled howler monkeys to anthropogenic noise. These results imply that management actions aimed at eradicating anthropogenic noise are required for the conservation and welfare of mantled howler monkeys at Los Tuxtlas.

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PURPOSE: After extraction, dental alveolus filling aims to reduce bone loss and maintain the alveolus volume during patient rehabilitation. Boric acid (BA) is a boron-derived compound with osteogenic properties and an interesting candidate for alveoli filling. This study aims to investigate the osteogenic capacity of the local application of BA in dental socket preservation. METHODS: Thirty-two male Wistar rats were submitted to upper right incisor extraction and randomly divided into four groups (n = 8): control group (no intervention), BA (8 mg/kg) socket filling, bone graft (Cerabone®, Botiss, Germany), and BA + bone graft socket filling. Animals were euthanized 28 days after dental extraction. MicroCT and histological analysis were performed to evaluate the newly formed bone on the dental alveolus. RESULTS: MicroCT analysis demonstrated that bone volume fraction (BV/TV), bone surface (BS), bone surface/bone volume ratio (BS/BV), bone surface density (BS/TV), trabecular thickness (Tb.Th), total bone porosity (Po-tot), and total volume of pore space (Po.V(tot)) from BA and BA + bone graft rats were significantly different from the control group. Histological evaluation displayed a delayed bone repair in BA rats, with the presence of connective tissue and inflammatory infiltrate. However, the BA + bone graft group demonstrated histological aspects like the bone graft animals, with less organized osteoblasts, suggesting inferior bone repair. CONCLUSION: Osteogenic capacity did not depend on the BA local application after 28 days of dental extraction. The presence of inflammation in the BA group can represent toxicity induced by the substance dosage used.

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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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Recently, the pharmaceutical industry has increasingly adopted the Analytical Quality by Design (AQbD) approach for analytical development. To facilitate AQbD approach implementation in the development of chromatographic methods for determining cephalosporin antibiotics, an in silico tool capable of performing virtual DoEs was developed enabling to obtain virtual operable regions of method. To this end, the drugs cephalexin, cefazolin, cefotaxime and ceftriaxone were analyzed using four experimental designs, deriving a DoE-QSRR model and employing Monte Carlo method. The DoE-QSRR model and virtual DoEs were validated using data not used in model's construction, obtaining coefficients of determination of 84.72 % for DoE-QSRR model and over 77 % for virtual DoEs. Virtual MODRs were constructed using data from the virtual DoEs. The virtual MODRs were validated by comparing them with experimental MODRs under various scenarios, with overlap areas reaching values exceeding 84 %. Therefore, the in silico tool was considered suitable for indicating analyte trends under different analytical conditions, being capable of performing virtual DoEs for cephalosporin drugs with sufficient assertiveness to guide analytical development and allow obtaining a MODR capable of providing results of adequate quality.

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Hydrogel filaments were manufactured using wet spinning technique, incorporating variations in the concentrations of sodium alginate, gelatin, and calcium chloride (crosslinking agent). The combination of biopolymer concentrations was determined using design of experiments (DoE) approach. The resulting filaments were produced from the developed hydrogels. Tensile and vertical strength analyses of the filaments were conducted using an electromechanical extensor. Atomic force microscopy was employed to evaluate the roughness, viscoelasticity, retraction, and deflection of the hydrogels. By employing DoE, a total of seventeen different combinations of biopolymers and crosslinkers were generated to construct the hydrogels. The filaments exhibited variations in electromechanical traction (measured in kPa) and produced distinct stress peaks. Furthermore, diverse roughness values were observed among the tested materials, with the combinations featuring higher concentrations of sodium alginate displaying the highest Young's modulus. This study demonstrates that manipulating the concentrations of biopolymers and crosslinking agents can modulate the micro and nanomechanical properties of biopolymeric filaments.

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Among defenses against predation, chemical defenses are possibly the most studied. However, when addressing the effectiveness of those chemical defenses, previous studies did not include properties of the chemical substances themselves. Lipophilicity, for instance, may facilitate crossing membranes, and boiling point may define the duration of the substances in the air. Moreover, other variables may also be relevant: the predator taxon; the prey model chosen to conduct experiments; whether the prey is presented grouped or not in experiments; and whether the chemical defense is a mixture of many substances or only one. To understand how those factors influence chemical defenses' effectiveness, we conducted a multilevel meta-analysis with 43 studies (127 effect sizes), accounting for different types of dependence. We used Akaike Information Criterion (AICc) to select the best model. The model with the lowest AICc value included only the boiling point, which defines how quickly a chemical substance volatilizes. This model indicated that the most effective chemical defenses had lower boiling point values, i.e., higher volatility. Moreover, we did not find chemicals with very low boiling points, suggesting there might be an optimum range of volatility. Other models, including the intercept-only model, were also recovered among the best models, therefore further studies are needed to confirm the relationship between volatility and chemical defenses' effectiveness. Our results highlight the value of incorporating physicochemical properties in the ecological and evolutionary study of chemical defense.

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The lack of data regarding infant exposure to drugs of abuse consumed by lactating mothers has become a major health concern. Investigating psychoactive substances and their metabolites in breastmilk is an analytical approach to estimate the rate at which drugs of abuse are excreted and how much infants are exposed to them. In this study, we have developed and validated a GC-MS method using disposable pipette tips for simultaneously extracting ten analytes from breastmilk samples obtained from a milk bank in the city of Ribeirão Preto, Brazil. All the 67 analyzed samples tested negative for all the analytes. This is the first study that has applied disposable pipette extraction to analyze drugs of abuse in breastmilk samples.

Breastfeeding, the most effective single strategy to reduce child mortality, provides numerous benefits for both the mother and the infant. The mother's consumption habits during breastfeeding strongly influence breastmilk quality and the newborn's nutrition. Given that drugs of abuse negatively affect both the mother's and the infant's health, analyzing breastmilk samples helps to estimate infant exposure to these drugs and to evaluate how severe this public health issue is. We have developed a new method to monitor ten substances in breastmilk, to improve our understanding of this issue in Brazil. None of the substances were detected in the few samples obtained from a milk bank, which showed that this organization successfully analyzes the donor's profile and conducts effective anamnesis. Future analysis of a larger number of samples and hence more data could help to describe the current scenario in more detail.

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Lung cancer is the leading cause of cancer-related death. In addition to new innovative approaches, practical strategies that improve the efficacy of already available drugs are urgently needed. In this study, an inhalable dry powder formulation is used to repurpose flubendazole, a poorly soluble anthelmintic drug with potential against a variety of cancer lineages. Flubendazole nanocrystals were obtained through nanoprecipitation, and dry powder was produced by spray drying. Through fractional factorial design, the spray drying parameters were optimized and the impact of formulation on aerolization properties was clarified. The loading limitations were clarified through response surface methodology, and a 15% flubendazole loading was feasible through the addition of 20% L-leucine, leading to a flubendazole particle size of 388.6 nm, median mass aerodynamic diameter of 2.9 µm, 50.3% FPF, emitted dose of 83.2% and triple the initial solubility. Although the cytotoxicity of this formulation in A549 cells was limited, the formulation showed a synergistic effect when associated with paclitaxel, leading to a surprising 1000-fold reduction in the IC50. Compared to 3 cycles of paclitaxel alone, a 3-cycle model combined treatment increased the threshold of cytotoxicity by 25% for the same dose. Our study suggests, for the first time, that orally inhaled flubendazole nanocrystals show high potential as adjuvants to increase cytotoxic agents' potency and reduce adverse effects.

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The ubiquity of microplastics has caused alarm as to the impact of these materials on aquatic life, leading to experimental studies to understand these effects. In zooplankton bioassays, microspheres (Ms) are often used as a proxy to represent aquatic microplastic contamination due to their homogeneity and small sizes (<100 µm). The present study proposes an accessible protocol that does not require highly specialized equipment for the creation of Ms stock solutions and environmentally realistic experimental concentrations and describes some common issues. Adult females of the calanoid copepod Centropages furcatus underwent treatments of two Ms sizes at experimental concentrations of 10 Ms/mL. They consumed on average 0.9 ± 2.6 Ms/mL of 45-53 µm Ms, and 2.4 ± 1.1 Ms/mL of 38-45 µm Ms. The results are not directly comparable with other studies due to the wide variety of methods used but successfully demonstrate the reproducibility of the proposed protocol.

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This study employed computational modeling (in silico) methods, combined with ecotoxicological experiments (in vivo) to predict the persistence/biodegradability, bioaccumulation, mobility, and ecological risks of an antihistamine drug (Loratadine: LOR) in the aquatic compartment. To achieve these goals, four endpoints of the LOR were obtained from different open-source computational tools, namely: (i) "STP total removal"; (ii) Predicted ready biodegradability; (iii) Octanol-water partition coefficient (KOW); and (iv) Soil organic adsorption coefficient (KOC). Moreover, acute and chronic, ecotoxicological assays using non-target freshwater organisms of different trophic levels (namely, algae Pseudokirchneriella subcapitata; microcrustaceans Daphnia similis and Ceriodaphnia dubia; and fish Danio rerio), were used to predict the ecological risks of LOR. The main results showed that LOR: (i) is considered persistent (after a weight-of-evidence assessment) and highly resistant to biodegradation; (ii) is hydrophobic (LOG KOW = 5.20), immobile (LOG KOC = 5.63), and thus, it can potentially bioaccumulate and/or can cause numerous deleterious effects in aquatic species; and (iii) after ecotoxicological evaluation is considered "toxic" and/or "highly toxic" to the three trophic levels tested. Moreover, both the ecotoxicological assays and risk assessment (RQ), showed that LOR is more harmful for the crustaceans (RQcrustaceans = moderate to high risks) than for algae and fish. Ultimately, this study reinforces the ecological concern due to the indiscriminate disposal of this antihistamine drug in worldwide aquatic ecosystems.

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Albendazole is a broad-spectrum anthelmintic drug used for parasitic infections. In addition, due to its mechanism of action, it has been studied as an anticancer agent. However, poor and highly variable bioavailability are limiting factors for its use in systemic illnesses. The present study aimed to develop two parenteral formulations of albendazole and to compare its pharmacokinetic profile with the conventional oral administration. Parenteral formulations were developed using two different approaches: a phosphonooxymethylated prodrug and cosolvents. For the albendazole prodrug, once synthetized, its solubility and hydrolysis with alkaline phosphatase were evaluated. A factorial design of experiments was used for the cosolvent formulation. Stability and hemolytic activity were assessed. A pharmacokinetic study was performed on New Zealand rabbits. Both formulations were administered intravenously, and the prodrug was also administered intramuscularly. Results were compared with those obtained after the oral administration of albendazole. A 20,000-fold and 6000-fold increase in albendazole solubility was found with the prodrug and cosolvent formulations, respectively. Both parenteral formulations displayed higher albendazole plasma concentrations for the first 2 h compared with oral administration, even when the oral dose was doubled. The absolute bioavailability of oral albendazole was 15.5% while for the intramuscular administration of the prodrug was 102.6%. Both parenteral formulations showed a significant decrease in the formation of albendazole sulfoxide (ANOVA p<0.05) and allowed greater exposure to albendazole. Albendazole cosolvent parenteral formulation could be a promising option in systemic illnesses considering its ease of preparation and superb pharmacokinetic performance.

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