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The use of near infrared (NIR) spectroscopy to predict the concentration of two active pharmaceutical ingredients (APIs), paracetamol and caffeine, in intact tablets, has been evaluated in this study. A partial least squares (PLS) regression model was developed using spectral data obtained on a calibration set consisting of 28 formulations containing 80, 90, 100, 110 and 120% of each API. Regression models were developed for each API, both using un-processed spectral data as well as after applying various spectra pre-processing methods. Cross-validation was used to select best calibration model. The selected model was validated in terms of precision, trueness, accuracy and linearity in a concentration ranging from 90 to 110% of the targeted APIs concentration. The applicability of the method was tested on tablets containing 300 mg paracetamol and 30 mg caffeine as targeted composition, and the API content predicted by the proposed NIR-chemometric method was not statistically different from the one obtained by HPLC method, used as a reference method. Thus, the method presented in the current paper is a step forward towards the implementation NIR as useful tool for monitoring the manufacturing process of fixed-dose combination tablets with paracetamol and caffeine.

The purpose of this research was to apply near-infrared (NIR) spectroscopy in combination with chemometrics to predict particle size and flow characteristics of a meloxicam powder blends for tableting. In order to develop calibration models for particle size (mean particle size, poly-dispersion index), and flow properties (angle of repose and time of flow) prediction, the NIR reflection spectra of different meloxicam powder blends prepared according to an experimental design were analyzed using different preprocessing methods by partial last-square (PLS) regression followed by leaveone-out cross-validation. Very good prediction ability was found for mean particle size, poly-dispersion index, angle of repose, and time of flow in models in whose development no preprocessing spectrum was applied. Also, a good prediction was found preprocessing spectrum such smoothing - moving average for particle size characteristics, and unit vector normalization for powder flow properties. Therefore, NIR-chemometric methods developed in this work can be useful for the prediction of the granulometric properties and parameters related to the flowability of the meloxicam powder blends and may be used as process analytical technology (PAT) tools for process control during meloxicam tablets manufacturing.

Statins, which are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, reduce cholesterol blood levels and the risk of developing cardiovascular diseases and their related complications. In addition to this main activity, statins show pleiotropic effects such as antioxidant, anti-inflammatory and antiproliferative properties, with applications in many pathologies. Based on their antiproliferative properties, in vitro and in vivo studies have investigated their effects on various types of cancer (i.e., breast cancer, prostate cancer, colorectal cancer, ovarian cancer, lung cancer) with different genetic and molecular characteristics. Many positive results were obtained, but they were highly dependent on the physiochemical properties of the statins, their dose and treatment period. Combined therapies of statins and cytotoxic drugs have also been tested, and synergistic or additive effects were observed. Moreover, observational studies performed on patients who used statins for different pathologies, revealed that statins reduced the risk of developing various cancers, and improved the outcomes for cancer patients. Currently, there are many ongoing clinical trials aimed at exploring the potential of statins to lower the mortality and the disease-recurrence risk. All these results are the foundation of new treatment directions in cancer therapy.

Objectives. The aim of this study was to optimize the formulation of certain immediate release foaming vaginal tablets, with fast vaginal disintegration (part I), fallowing their time stability (part II). Material and methods. Modde optimizing software and a Box-Bhenken experimental design was used to establish an optimal formula that would provide maximum “in vitro” behaviour advantages, including stability during preservation; and the improvement of the foaming effect. There were prepared 15 formulations of foaming vaginal tablets in order to choose the optimal formula. Outcomes. The main factor, with influence over all the studied parameters, is the percentage of the effervescent mixture in the formulation. The excess of citric acid has a main role in the assurance of local pH; in the improvement of the flowing properties of the powder mixtures before compression; and in the improvement of the effervescent process, having, on the other hand, an effect of decreasing the stability of tablets and increasing their humidity adsorption. Sodium lauryl sulphate, at the chosen concentration levels (0.5-1.5%), did not influence the dependent variables, it only produced a stronger resistance of the foam. The optimal formula of a foaming vaginal tablet with an optimal stability during preservation must contain 0.5% sodium lauryl sulphate, while the effervescent mixture must contain a percentage of 24% excess of citric acid, and it must represent 44% of the total amount of excipients. Conclusions. The experimental determinations of the optimal formula were close to the theoretical values predicted by the program, this certifying the validity of the optimization and the conclusion draw after analysis the experimental design.

Objectives. The aim of this study was to develop and validate a NIR-chemometric method for direct quantification of loratadine in powder blends for tableting and tablets, without any sample preparation. Material and methods. Calibration samples were prepared according to an experimental design with 1 variable and 5 level, containing from 8 to 12 mg loratadine/tablet. Outcomes. For the powder blends, the model generated with the use of spectral range 9,000-4,000 cm-1 and FD+SNV pre-treatment method had the best results, considering the number of PLS factors 9, R2 = 0.984 and RMSECV = 0.267%. For the tablets, the model using the spectral range 11,100-7,128 cm-1 and mMN pre-treatment method had the best results, considering the number of PLS factors 10, R2 = 0.985 and RMSECV = 0.170 mg. Using these calibration models, the method was fully validated according to the ICH guidance. For both powder blends and tablets, the best accuracy was obtained at the concentration level of 10 mg/tablet and the relative bias had values between 0.05% and 1.98% respectively -0.360% and 0.618%. Conclusions. The NIR-chemometric method has good reproducibility and satisfactory accuracy and linearity profiles, indicating that this method could be used for direct determination of loratadine in powder blends for tableting and tablets, without any sample preparation.

5‐Fluorouracil‐based therapy remains the main approach in colorectal cancer, even though there are still some drawbacks, such as chemoresistance. In this study we combined 5‐fluorouracil encapsulated in long‐circulating liposomes with simvastatin, also encapsulated in long‐circulating liposomes, that was previously proved to exert antitumor actions on the same tumor model. The production of angiogenic/inflammatory proteins was assessed by protein array and the production of markers for tumor aggressiveness (Bcl‐2, Bax, and nuclear factor [NF]‐κB) were determined by western blot analysis. Intratumor oxidative stress was evaluated through measurement of malondialdehyde level by HPLC, and through spectrophotometric analysis of catalytic activity of catalase and of total antioxidant capacity. Immunohistochemical analysis of tumors for CD31 expression was assessed. Intratumor activity of MMP‐2 by gelatin zymography was also carried out. Our results revealed that combined therapies based on liposomal formulations exerted enhanced antitumor activities compared with combined treatment with free drugs. Sequential treatment with liposomal simvastatin and liposomal 5‐fluorouracil showed the strongest antitumor activity in C26 colon carcinoma in vivo, mainly through inhibition of tumor angiogenesis. Important markers for cancer progression (Bcl‐2, Bax, NF‐κB, and intratumor antioxidants) showed that liposomal simvastatin might sensitize C26 cells to liposomal 5‐fluorouracil treatment in both regimens tested. The outcome of simultaneous treatment with liposomal formulations was superior to sequential treatment with both liposomal types as the invasive capacity of C26 tumors was strongly increased after the latest treatment. The antitumor efficacy of combined therapy in C26 colon carcinoma might be linked to the restorative effects on proteins balance involved in tumor angiogenesis., Liposomal simvastatin sensitizes C26 cells to liposomal 5‐fluorouracil treatment. The combination therapy based on the administration of liposomal simvastatin and 5‐fluorouracil has the potential to become a successful cancer‐targeted therapy, mainly due to the inhibitory effects on the intratumor angiogenesis.

The study focused on the fluid-bed granulation process of a product with two active pharmaceutical ingredients, intended for coated tablets preparation and further transfer to industrial scale. The work aimed to prove that an accurate control of the critical granulation parameters can level the input material variability and offer a user-friendly process control strategy. Moreover, an in-line Near-Infrared monitoring method was developed, which offered a real time overview of the moisture level along the granulation process, thus a reliable supervision and control process analytical technology (PAT) tool. The experimental design's results showed that the use of apparently interchangeable active pharmaceutical ingredients (APIs) and filler sorts that comply with pharmacopoeial specifications, lead to different end-product critical attributes. By adapting critical granulation parameters (i.e. binder spray rate and atomising pressure) as a function of material characteristics, led to granules with average sizes comprised in a narrow range of 280–320 µm and low non-granulated fraction of under 5%. Therefore, the accurate control of process parameters according to the formulation particularities achieved the maintenance of product within the design space and removed material related variability. To complete the Quality by design (QbD) strategy, despite its limited spectral domain, the microNIR spectrometer was successfully used as a robust PAT monitoring tool that offered a real time overview of the moisture level and allowed the supervision and control of the granulation process., Graphical abstract Image, graphical abstract

The extraction of bioactive compounds present in walnut (Juglans regia L.) male flowers (WMFs) was performed based on an experimental design using ultrasonic-assisted extraction. Solvent nature, extraction time, and water content were selected as experimental variables, and phenolic, flavonoidic, and condensed tannins contents and antioxidant properties were evaluated. Acetone was the solvent with the highest extraction performance, with the extracts obtained using this solvent displaying an increased concentration of bioactive compounds and increased antioxidant activities. For several extracts with high bioactive content, individual polyphenolic and tocopherolic compounds were evaluated by means of LC-MS and LC-MS/MS. The best extraction conditions for polyphenolic (2.86 mg gallic acid equivalents/g WMF) and tocopherolic compounds (29.4 µg/g WMF) were acetone with 40% water content (N20) and acetone with 20% water content (N15), respectively. Although the total tocopherol concentrations were lower than in other Juglans regia parts, most of the total tocopherol quantity was provided by the highly biologically active δ-tocopherol (84%). Significant quantities of quercetin (101.9 µg/g), hyperoside (2662.9 µg/g), quercitrin (405.7 µg/g), and isoquercitrin (1293.7 µg/g) were determined in WMF (N20). Both extracts inhibited the enzymatic activity of α-glucosidase and tyrosinase, however, an increased inhibition was observed for N20, the extract with the higher polyphenolic content. Conversely, N15 had higher anticancerous activity on the cell lines used, with a moderate selectivity towards the cancerous phenotype being observed for both extracts. At non-cytotoxic concentrations, both extracts displayed good antioxidant activities in cellular cultures, decreasing basal and H2O2-induced oxidative stress. This is the first characterization of both hydrophilic and lipophilic phytochemicals in WMF extracts. The outcomes of our study reveal that walnut male flowers have strong biological activities, thus justifying further research to demonstrate their usefulness in the food, pharmaceutical, and/or cosmetic industries.

(1) Background: Portable NIR spectrometers gain more and more ground in the field of Process Analytical Technology due to the easy on-site flexibility and interfacing versatility. These advantages that originate from the instrument miniaturization, also come with a downside with respect to performance compared to benchtop devices. The objective of this work was to evaluate the performance of MicroNIR in a pharmaceutical powder blend application, having three active ingredients and 5 excipients. (2) Methods: Spectral data was recorded in reflectance mode using static and dynamic acquisition, on calibration set samples developed using an experimental design. (3) Results: The developed method accurately predicted the content uniformity of these complex mixtures, moreover it was validated in the entire calibration range using ±10% acceptance limits. With respect to at-line prediction, the method presented lower performance compared to a previously studied benchtop spectrometer. Regarding the in-line monitoring of the blending process, it was shown that the spectral variability-induced by dynamic acquisition could be efficiently managed using spectral pre-processing. (4) Conclusions: The in-line process monitoring resulted in accurate concentration profiles, highlighting differences in the mixing behaviour of the investigated ingredients. For the low dose component homogeneity was not reached due to an inefficient dispersive mixing.

Purpose: Besides cholesterol lowering effects, simvastatin (SIM) at very high doses possesses antitumor actions. Moreover our previous studies demonstrated that tumor-targeted delivery of SIM by using long-circulating liposomes (LCL) improved the therapeutic index of this drug in murine melanoma-bearing mice. To evaluate whether this finding can be exploited for future therapy of colorectal cancer the antitumor activity and the underlying mechanisms of long-circulating liposomal simvastatin (LCL-SIM) efficacy for inhibition of C26 murine colon carcinoma growth in vivo were investigated. Materials and Methods: To find LCL-SIM dose with the highest therapeutic index, dose-response relationship and side effects of different LCL-SIM doses were assessed in C26 colon carcinoma-bearing mice. The underlying mechanisms of LCL-SIM versus free SIM treatments were investigated with regard to their actions on C26 cell proliferation and apoptosis (via tumor tissues immunostaining for PCNA and Bax markers), tumor inflammation (via western blot analysis of NF-κΒ production), angiogenesis (using an angiogenic protein array), and oxidative stress (by HPLC assessment of malondialdehyde). Results: Our findings suggest that LCL-SIM antitumor activity on C26 colon carcinoma is a result of the tumor-targeting property of the liposome formulation, as free SIM treatment was ineffective. Moreover, LCL-SIM exerted significant antiproliferative and pro-apoptotic actions on C26 cells, notable suppressive effects on two main supportive processes for tumor development, inflammation and angiogenesis, and only slight anti-oxidant actions. Conclusion: Our data proved that LCL-SIM antitumor activity in C26 colon carcinoma was based on cytotoxic effects on these cancer cells and suppressive actions on tumor angiogenesis and inflammation.

Sonia Iurian, Luana Turdean, Ioan Tomuta Department of Pharmaceutical Technology and Biopharmacy, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania Abstract: This study focuses on the development of a drug product based on a risk assessment-based approach, within the quality by design paradigm. A prolonged release system was proposed for paliperidone (Pal) delivery, containing Kollidon® SR as an insoluble matrix agent and hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), or sodium carboxymethyl cellulose as a hydrophilic polymer. The experimental part was preceded by the identification of potential sources of variability through Ishikawa diagrams, and failure mode and effects analysis was used to deliver the critical process parameters that were further optimized by design of experiments. A D-optimal design was used to investigate the effects of Kollidon SR ratio (X1), the type of hydrophilic polymer (X2), and the percentage of hydrophilic polymer (X3) on the percentages of dissolved Pal over 24 h (Y1–Y9). Effects expressed as regression coefficients and response surfaces were generated, along with a design space for the preparation of a target formulation in an experimental area with low error risk. The optimal formulation contained 27.62% Kollidon SR and 8.73% HPMC and achieved the prolonged release of Pal, with low burst effect, at ratios that were very close to the ones predicted by the model. Thus, the parameters with the highest impact on the final product quality were studied, and safe ranges were established for their variations. Finally, a risk mitigation and control strategy was proposed to assure the quality of the system, by constant process monitoring. Keywords: pharmaceutical development, quality by design, failure mode effects analysis, Ishikawa diagram, fish-bone diagram, hydrophilic matrix

The main objective of the present study was to apply QbD methodology in the development of once-a-day sustained release quetiapine tablets. The quality target product profile (QTPP) was defined after the pharmaceutical properties and kinetic release of the innovator product, Seroquel XR 200 mg. For the D-optimal experimental design, the level and ratio of matrix forming agents and the type of extragranular diluent were chosen as independent inputs, which represented critical formulation factors. The critical quality attributes (CQAs) studied were the cumulative percentages of quetiapine released after certain time intervals. After the analysis of the experimental design, optimal formulas and the design space were defined. Optimal formulas demonstrated zero-order release kinetics and a dissolution profile similar to the innovator product, with f2 values of 74.53 and 83.74. It was concluded that the QbD approach allowed fast development of sustained release tablets with similar dissolution behavior as the innovator product.

Striae distensae are a frequent skin condition associated with pregnancy, weight change or lack of skin elasticity. The aim of this research was to obtain a topical product containing herbal active ingredients with documented antioxidant and anti-inflammatory activity (Punica granatum seed oil and Croton lechleri resin extract) and demonstrate its positive effect on prevention and treatment of striae distensae. First, the cream base formulation was optimized through experimental design. Secondly, the cream containing the two active ingredients was investigated in an interventional nonrandomized clinical trial. The clinical outcome was assessed through biophysical parameters and ultrasonographic evaluation. The state of the skin was evaluated by biophysical measurements and ultrasonography at the beginning of the study and after 3 and 6 weeks. The experimental design was successfully used to set the best ranges for the technological and formulation factors to obtain a cosmetic formulation with optimal characteristics. The study of clinical efficacy on the optimal formulation revealed an increase in the dermis thickness, hydration and elasticity values in both groups after 6 weeks of cream application. The new oil-in-water cream containing P. granatum seed oil and C. lechleri resin extract can be helpful in the prevention or improving of skin changes associated with striae.

Tree nut by-products could contain a wide range of phytochemicals, natural antioxidants, which might be used as a natural source for dietary supplements. The aim of the present study was to evaluate the phenolic and sterolic composition, as well as the antioxidant and other biological activities, of hazelnut involucre (HI) extracts. Experimental designs were developed in order to select the optimum extraction conditions (solvent, temperature, time) using turbo-extraction by Ultra-Turrax for obtaining extracts rich in bioactive compounds. Qualitative and quantitative analyses were performed by LC-MS and LC-MS/MS and they revealed important amounts of individual polyphenols and phytosterols, molecules with antioxidant potential. The richest polyphenolic HI extract with the highest antioxidant activity by TEAC assay was further evaluated by other in vitro antioxidant tests (DPPH, FRAP) and enzyme inhibitory assays. Additionally, the cytotoxic and antioxidant effects of this extract on two cancerous cell lines and on normal cells were tested. This is the first study to analyze the composition of both hydrophilic and lipophilic bioactive compounds in HI extracts. Our findings reveal that this plant by-product presents strong biological activities, justifying further research, and it could be considered an inexpensive source of natural antioxidants for food, pharmaceutical, or cosmetic industry.

Plant by-products can be valuable sources of polyphenol bioactive compounds. Walnut (Juglans regia L.) is a very important tree nut rich in biologically active molecules, but its septum was scarcely researched. Experimental data indicated a hypoglycemic effect of septum extracts, with almost no details about its phytochemical composition. The main objectives of this study were: (1) to obtain walnut septum (WS) extracts with high content in bioactive compounds and antioxidant activity based on an original experimental design, (2) characterization of the phytochemical profile of the WS extracts using HPLC-MS/MS, (3) evaluation of the biological potential of the richest polyphenolic WS extract. The variables of the experimental design were: extraction method (maceration and Ultra-Turrax extraction), temperature, solvent (acetone and ethanol), and percentage of water in the solvent. The first quantifiable responses were: total phenolic content, total flavonoid content, condensed tannins, and ABTS antioxidant capacity. The phytochemical profile of lyophilized extracts obtained by Ultra-Turrax extraction (UTE), the most efficient method, was further determined by HPLC-MS/MS analysis of individual polyphenolic and phytosterols compounds. It is the first study to assay the detailed composition of WS in hydrophilic and lipophilic compounds. The biological potential of the richest polyphenolic WS extract was also evaluated by FRAP and DPPH antioxidant capacity and the inhibition of tyrosinase, an enzyme involved in the browning in fruits and vegetables, skin wrinkles and aging. Conclusion: The phytochemical profile of the analyzed extracts proves that WS can be a valuable source of biologically active compounds (polyphenols) for food and/or pharmaceutical industry and warrant the continuation of current research in further evaluating its bioactive potential.

Objective: Design of Experiment (DoE), that is a tool of Quality by Design (QbD) paradigm, with which experiments can be planned more effectively and provide more information, while after Design Space (DS) can be set up, which assure the quality of the desired product. The aim of this study was to find the optimal drug-excipient ratio and the optimal process parameters (milling time, milling speed) of our previously used dry co-milling method and validate the DS. Materials and methods: Lamotrigine (LAM), an antiepileptic drug was used as a model API. Poly-vinyl alcohol (PVA) was chosen according to our previous study as a hydrophylic matrix polymer. Milling time, speed, and the API:additive ratio was varied to find out their effect on the product. The optimization was performed on particle size of LAM, its standard deviation and the in vitro dissolution of the samples. Response surface modeling completed the statistical analysis that assessed the effects of independent variables on the responses. Results: Due to the DS estimation, a more economical sample preparation method was set up. Finally, the sample that was prepared according to the optimized parameters (1.5 h, 400 rpm, 0.8 PVA:LAM ratio) showed around 100 nm drug particles and 97% drug release in five minutes. Conclusion: From the DS generated by the software, an optimal formulation was obtained and the results validated the experimental design. The QbD approach was a useful and effective tool of understanding the parameters that affect the quality of the desired product.

The antitumor efficacy of 5-fluorouracil (5-FU) in advanced colorectal cancer (CRC) is hindered not only by the low therapeutic index, but also by tumor cell resistance to this cytotoxic drug. Therefore, to enhance the 5-FU antitumor activity, the present research used a novel tumor-targeted therapy based on the co-administration of 5-FU encapsulated in long-circulating liposomes (LCL-5-FU) together with liposomal prednisolone phosphate (LCL-PLP), a formulation with known anti-angiogenic actions on C26 murine colon carcinoma cells. Thus, we assessed the in vivo effects of the combined liposomal drug therapy on C26 carcinoma growth as well as on the production of molecular markers with key roles in tumor development such as angiogenic, inflammatory, and oxidative stress molecules. To get further insight into the polarization state of tumor microenvironment after the treatment, we determined the IL-10/IL-12p70 ratio in tumors. Our results showed that combined liposomal drug therapy inhibited almost totally tumor growth and was superior as antitumor activity to both single liposomal drug therapies tested. The antitumor efficacy of the combined therapy was mainly related to the anti-angiogenic and anti-inflammatory actions on C26 carcinoma milieu, being favored by its controlling effect on intratumor oxidative stress and the skewing of polarization of tumor microenvironmental cells toward their antineoplastic phenotypes. Thus, our study unveils a promising treatment strategy for CRC that should be furthermore considered.

Lucia Ruxandra Tefas,1 Bianca Sylvester,1 Ioan Tomuta,1 Alina Sesarman,2,3 Emilia Licarete,2,3 Manuela Banciu,2,3 Alina Porfire1 1Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, University of Medicine and Pharmacy “Iuliu Hatieganu”, 2Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, 3Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babeş-Bolyai University, Cluj-Napoca, Romania Abstract: The aim of this work was to use the quality-by-design (QbD) approach in the development of long-circulating liposomes co-loaded with curcumin (CUR) and doxorubicin (DOX) and to evaluate the cytotoxic potential of these liposomes in vitro using C26 murine colon carcinoma cell line. Based on a risk assessment, six parameters, namely the phospholipid, CUR and DOX concentrations, the phospholipid:cholesterol molar ratio, the temperature during the evaporation and hydration steps and the pH of the phosphate buffer, were identified as potential risk factors for the quality of the final product. The influence of these variables on the critical quality attributes of the co-loaded liposomal CUR and DOX was investigated: particle size, zeta potential, drug loading and entrapment efficiency. For this, a 26-2 factorial design was employed to establish a proper regression model and to generate the contour plots for the responses. The obtained data served to establish the design space for which different combinations of variables yielded liposomes with characteristics within predefined specifications. The validation of the model was carried out by preparing two liposomal formulations corresponding to the robust set point from within the design space and one outside the design space and calculating the percentage bias between the predicted and actual experimental results. The in vitro antiproliferative test showed that at higher CUR concentrations, the liposomes co-encapsulating CUR and DOX had a greater cytotoxic effect than DOX-loaded liposomes. Overall, this study showed that QbD is a useful instrument for controlling and optimizing the manufacturing process of liposomes co-loaded with CUR and DOX and that this nanoparticulate system possesses a great potential for use in colon cancer therapy. Keywords: doxorubicin, curcumin, co-loaded long-circulating liposomes, quality by design, design of experiments

Near-infrared spectroscopy (NIRS) is a technique widely used for rapid and nondestructive analysis of solid samples. A method for simultaneous analysis of the two components of paracetamol and caffeine from powder blends has been developed by using chemometry with near-infrared spectroscopy (NIRS). The method development was performed on samples containing 80, 90, 100, 110, and 120% active pharmaceutical ingredients, and near-infrared spectroscopy (NIRS) spectra of prepared powder blends were recorded and analyzed in order to develop models for the prediction of drug content. Many calibration models were applied in order to perform quantitative determination of drug content in powder, and choosing the appropriate number of factors (principal components) proved to be of highly importance for a PLS chemometric calibration. Once the methods were developed, they were validated in terms of trueness, precision, and accuracy. The results obtained by NIRS methods were compared with those obtained by HPLC reference method, and no significant differences were found. Therefore, the NIR chemometry methods were proved to be a suitable tool for predicting chemical properties of powder blends and for simultaneous determination of active pharmaceutical ingredients.

The main objective of the present study was to apply QbD methodology in the development of once-a-day sustained release quetiapine tablets. The quality target product profile (QTPP) was defined after the pharmaceutical properties and kinetic release of the innovator product, Seroquel XR 200 mg. For the D-optimal experimental design, the level and ratio of matrix forming agents and the type of extragranular diluent were chosen as independent inputs, which represented critical formulation factors. The critical quality attributes (CQAs) studied were the cumulative percentages of quetiapine released after certain time intervals. After the analysis of the experimental design, optimal formulas and the design space were defined. Optimal formulas demonstrated zero-order release kinetics and a dissolution profile similar to the innovator product, with f2 values of 74.53 and 83.74. It was concluded that the QbD approach allowed fast development of sustained release tablets with similar dissolution behavior as the innovator product.

The International Civic and Citizenship Study investigates the role of schooling in preparing students for their roles as citizens. The present paper tests a model in which openness in classroom discussion is a school factor that can affect civic knowledge. A multilevel regression model with two levels was tested considering the ICSS-scaled score for civic knowledge as a dependent variable and students’ perceptions of openness in classroom discussion as an independent variable at the school level. Various control variables were analyzed. Students’ civic knowledge scores resulted significantly higher if in their school there was an open classroom climate for discussion.