Papers by Mafalda Sarraguça
International Journal of Molecular Sciences
Tuberculosis is an infectious disease caused by the bacterial complex Mycobacterium tuberculosis.... more Tuberculosis is an infectious disease caused by the bacterial complex Mycobacterium tuberculosis. Despite the decline in the incidence and mortality of this disease over the years, the emergence of new strains of tuberculosis resistant to existing tuberculostatic drugs is currently one of the largest public health problems. The engineering and development of new drugs is a complex process; therefore, the modification and enhancement of the drugs already marked is a better and faster solution. Ethambutol (ETB) is an antimycobacterial drug used to treat tuberculosis; however, it is highly hygroscopic and is sparingly soluble in water. Therapeutic Deep Eutectic Solvents (THEDESs) are known to improve drug solubility, permeability, and hygroscopicity, among others. In this study, three THEDESs of ETB were synthesized with sucralose, glucose and glycerol and then encapsulated in nanostructured lipid carriers to improve their stability. This work is a proof of concept on the possibility o...
Molecules
With the increase in the world population, the overexploitation of the planet’s natural resources... more With the increase in the world population, the overexploitation of the planet’s natural resources is becoming a worldwide concern. Changes in the way humankind thinks about production and consumption must be undertaken to protect our planet and our way of living. For this change to occur, sustainable development together with a circular economic approach and responsible consumption are key points. Agriculture activities are responsible for more than 10% of the greenhouse gas emissions; moreover, by 2050, it is expected that food production will increase by 60%. The valorization of food waste is therefore of high importance to decrease the environmental footprint of agricultural activities. Fruits and vegetables are wildly consumed worldwide, and grapes are one of the main producers of greenhouse gases. Grape biomass is rich in bioactive compounds that can be used for the food, pharmaceutical and cosmetic industries, and their extraction from this food residue has been the target of ...
Sustainability
Meat consumption is estimated to increase worldwide, mostly because of the increase in population... more Meat consumption is estimated to increase worldwide, mostly because of the increase in population. Further, this increase in meat consumption will ultimately affect the environment and aggravate climate change. Herein, consumers’ behaviour was studied to understand if consumers would consider a change in their dietary habits by choosing beef from the Portuguese autochthonous bovine breed or even reducing their meat intake for environmental reasons. In 2021, a survey was conducted online and in some food sales outlets in Portugal. Therefore, data collected from the 491 participants were analysed with the aim of assessing the Portuguese consumer behaviour and preferences on beef. Firstly, we conducted a descriptive analysis. Then, factor analysis was performed by principal component analysis. Finally, by cluster analysis, we attempted to identify a group of consumers with different behaviours into specific categories. Although it was not possible to segregate consumers into different ...
Molecules
In Portugal, publications with mechanochemical methods date back to 2009, with the report on mech... more In Portugal, publications with mechanochemical methods date back to 2009, with the report on mechanochemical strategies for the synthesis of metallopharmaceuticals. Since then, mechanochemical applications have grown in Portugal, spanning several fields, mainly crystal engineering and supramolecular chemistry, catalysis, and organic and inorganic chemistry. The area with the most increased development is the synthesis of multicomponent crystal forms, with several groups synthesizing solvates, salts, and cocrystals in which the main objective was to improve physical properties of the active pharmaceutical ingredients. Recently, non-crystalline materials, such as ionic liquids and amorphous solid dispersions, have also been studied using mechanochemical methods. An area that is in expansion is the use of mechanochemical synthesis of bioinspired metal-organic frameworks with an emphasis in antibiotic coordination frameworks. The use of mechanochemistry for catalysis and organic and ino...
International Journal of Pharmaceutics, 2022
Among the strategies for bioavailability improvement of poorly soluble drugs, co-amorphous system... more Among the strategies for bioavailability improvement of poorly soluble drugs, co-amorphous systems have revealed to have a significant impact in the increase of the aqueous solubility of the drug, and at the same time increasing the amorphous state stability and dissolution rate when compared with the neat drug. Tolbutamide (TBM) is an oral hypoglycemic drug largely used in the treatment of type II Mellitus diabetes. TBM is a class II drug according to the Biopharmaceutical Classification System, meaning that it has low solubility and higher permeability. The aim of this study was to synthesize a co-amorphous material of tolbutamide (TBM) with tromethamine (TRIS). Density functional theory (DFT), allowed to study the structural, electronic, and thermodynamic properties, as well as solvation effects. In same theory level, several interactions tests were performed to obtain the most thermodynamically favorable drug-coformer intermolecular interactions. The vibrational spectra (mid infrared and Raman spectroscopy) are in accordance with the theoretical studies, showing that the main molecular interactions are due to the carbonyl, sulfonyl, and amide groups of TMB and the alcohol and amine groups of TRIS. X-ray powder diffraction was used to study the physical stability in dry condition at 25 °C of the co-amorphous system, indicating that the material remained in an amorphous state up to 90 days. Differential scanning calorimetry and thermogravimetric results showed a high increase of the Tg when compared with the amorphous neat drug, from 4.3 °C to 83.7 °C, which generally translated into good physical stability. Solubilities studies demonstrated an increase in the solubility of TBM by 2.5 fold when compared with its crystalline counterpart.
International Journal of Pharmaceutics, 2021
Multivariate Curve Resolution (MCR) was used to determine the phase purity of pharmaceutical co-c... more Multivariate Curve Resolution (MCR) was used to determine the phase purity of pharmaceutical co-crystals from mid infrared spectra. An in-silico coformer screening was used to choose one of ten potential coformers. This analysis used quantum chemistry simulation to predict which coformers are thermodynamically inclined to form cocrystals with the model drug, hydrochlorothiazide. The coformer chosen was nicotinamide. An experimental solvent screening by ultrasound assisted slurry co-crystallization was performed to evaluate the capacity of the method to determine phase purity. Afterwards, slurry and slow evaporation co-crystallizations were performed at 10, 25, and 40 °C using 7 solvent systems, and two levels of agitation for the evaporation co-crystallization (on and off). Mid infrared spectroscopy (MIRS) analysis of the products of these co-crystallizations was used to develop an MCR model to determine co-crystal phase purity. The MCR results were compared with a reference co-crystal. Experimental design (DoE) was used to investigate the effect of solvents, temperature, and agitation on the purity of co-crystals produced by slurry and evaporation co-crystallization. DoE revealed that evaporation co-crystallization with agitating at 65 rpm formed co-crystals with greater phase purity. The optimal temperature varied with the solvent used.
European Journal of Pharmaceutics and Biopharmaceutics, 2018
Environmental Geochemistry and Health, 2016
Mineral natural waters and spas have been used for therapeutic purposes for centuries, with Portu... more Mineral natural waters and spas have been used for therapeutic purposes for centuries, with Portugal being a very rich country in thermal waters and spas that are mainly distributed by northern and central regions where Beira Interior region is located. The use of thermal waters for therapeutic purposes has always been aroused a continuous interest, being dependent on physicochemical fingerprinting of this type of waters the indication for a treatment in a specific pathological condition. In the present work, besides a literature review about the physicochemical composition of the thermal waters of the Beira Interior region and its therapeutic indications, it was carried out an Keywords Thermal water Á Physicochemical composition Á Therapeutic indications Á Beira Interior Á Portugal Á Multivariate analysis Electronic supplementary material The online version of this article (
International Journal of Pharmaceutics, 2017
A multivariate statistical process control (MSPC) strategy was developed for the monitoring of th... more A multivariate statistical process control (MSPC) strategy was developed for the monitoring of the ConsiGma TM-25 continuous tablet manufacturing line. Thirty-five logged variables encompassing three major units, being a twin screw high shear granulator, a fluid bed dryer and a product control unit, were used to monitor the process. The MSPC strategy was based on principal component analysis of data acquired under normal operating conditions using a series of four process runs. Runs with imposed disturbances in the dryer air flow and temperature, in the granulator barrel temperature, speed and liquid mass flow and in the powder dosing unit mass flow were utilized to evaluate the model's monitoring performance. The impact of the imposed deviations to the process continuity was also evaluated using Hotelling's T 2 and Q residuals statistics control charts. The influence of the individual process variables was assessed by analyzing contribution plots at specific time points. Results show that the imposed disturbances were all detected in both control charts. Overall, the MSPC strategy was successfully developed and applied. Additionally, deviations not associated with the imposed changes were detected, mainly in the granulator barrel temperature control.
Natural Bioactive Compounds from Fruits and Vegetables as Health Promoters Part II, 2016
Journal of Molecular Liquids
Pharmaceuticals, 2022
The low solubility of active pharmaceutical ingredients (APIs) is a problem in pharmaceutical dev... more The low solubility of active pharmaceutical ingredients (APIs) is a problem in pharmaceutical development. Several methodologies can be used to improve API solubility, including the use of eutectic systems in which one of the constituents is the API. This class of compounds is commonly called Therapeutic Deep Eutectic Systems (THEDES). THEDES has been gaining attention due to their properties such as non-toxicity, biodegradability, and being non-expensive and easy to prepare. Since the knowledge of the solid liquid diagram of the mixture and the ideal eutectic point is necessary to ascertain if a mixture is a deep eutectic or just a eutectic mixture that is liquid at ambient temperature, the systems studied in this work are called Therapeutic Liquid Eutectic Systems (THELES). Therefore, the strategy proposed in this work is to improve the solubility of chlorpropamide and tolbutamide by preparing THELES. Both APIs are sulfonylurea compounds used for the treatment of type 2 diabetes m...
With the recent guidelines promoted by the major health authorities, combined in the Internationa... more With the recent guidelines promoted by the major health authorities, combined in the International Conference on Harmonization Guidelines Q8, Q9, and Q10, regulating the pharmaceutical development, risk management, and quality management systems, respectively, pharmaceutical process data and their appropriate handling become more relevant than never. The development of a drug product production process is steadily advancing toward the adoption of science-based approaches for better understanding of processes underlying mechanisms, aiming at minimizing product quality variability. The adoption of new technology for assessing the quality of pharmaceutical products in real time (process analytical technology tools) and new paradigms of production, such as continuous manufacturing, brings additional challenges for pharmaceutical data scientists. Finally, product conception and manufacturing processes development can no longer be considered apart from the concept of life-cycle management...
Free Radical Biology and Medicine, 2020
ABCC6, a member of the adenosine 5 0-triphosphate-binding cassette family of genes, encodes multi... more ABCC6, a member of the adenosine 5 0-triphosphate-binding cassette family of genes, encodes multidrug resistance-associated protein 6, a putative transmembrane transporter expressed primarily in the liver and to a significantly lower extent in other tissues. Mutations in ABCC6 result in pseudoxanthoma elasticum, a multisystem heritable connective tissue disorder with variable phenotypic expression. To examine the transcriptional regulation and tissue-specific expression of this gene, we cloned 2.6 kb of human ABCC6 promoter and developed a series of 5 0-deletion constructs linked to luciferase reporter gene. Transient transfections in a number of cultured cell lines of diverse origin identified a specific NF-kB-like sequence (À235/À226), which conferred high level of expression in HepG2 hepatoma cells, inferring liver specificity. The functionality of the promoter fragments was confirmed in vivo by tail vein injection followed by luciferase reporter assay. Testing of selected cytokines revealed that transforming growth factor (TGF)-b upregulated, while tumor necrosis factor (TNF)-a and interferon (IFN)-g downregulated the promoter activity in HepG2 cells. The responsiveness to TGF-b was shown to reside primarily within an Sp1/Sp3 cognate-binding site at À58 to À49. The expression of the ABCC6 promoter was also shown to be markedly enhanced by Sp1 protein, as demonstrated by cotransfection of ABCC6 promoter-luciferase constructs and an Sp1 expression vector in Drosophila SL2 cells, which are devoid of endogenous Sp1. Furthermore, four additional transcription factors, with their cognate-binding sequences present in DNA, were shown to bind the 2.6-kb promoter fragment by protein/DNA array. Collectively, the results indicate that human ABCC6 displays tissue-specific gene expression, which can be modulated by proinflammatory cytokines. These findings may have implications for phenotypic expression of heritable and acquired diseases involving abnormality in the ABCC6 gene.
Journal of Molecular Structure, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2019
For industrial production of cocrystals, screening phase is essential, helping to become the proc... more For industrial production of cocrystals, screening phase is essential, helping to become the process faster, more effective and efficient, reducing the quantity of reactants used and associated costs. High-throughput screening (HTS) methods can analyze a wide range of compounds simultaneously. As an answer to industrial necessity of more efficient screening methods, different methods must be developed and optimized. Vibrational spectroscopic techniques are fast, non-destructive and non-invasive, do not need pre-treatment of the samples and allow obtaining qualitative and quantitative information. They are useful in cocrystal analysis, once they detect weak interaction as hydrogen bonding, the basis of cocrystal formation. Therefore, its application in the analysis of cocrystal screening methods, together with multivariate analysis, should be studied in detail. For this end, a HTS procedure of hydrochlorothiazide (HTZ) cocrystals is performed using a 96-well plate and ultrasound-assisted cocrystallization. Six coformers were tested considering ratios of HTZ:coformer of 1:1 and 1:2. The cocrystallization products were analyzed by mid infrared spectroscopy and Raman microspectroscopy. Nicotinamide and p-aminobenzoic acid formed cocrystals with HTZ. The systems with arginine showed that the coformer suffered amorphization; however, no proof of the solid state of HTZ was obtained. The results were not conclusive for the system with citric acid. Additionally, in the nicotinamide and citric acid systems, the physical mixture of the plate also reacted without the present of solvent. Overall, the use of mid infrared spectroscopy and multivariate data analysis provided important information on cocrystal formation, purity, and correct ratio assessment.
Journal of pharmaceutical sciences, Jan 27, 2018
The present work presents an in-depth evaluation of continuously collected data during a twin-scr... more The present work presents an in-depth evaluation of continuously collected data during a twin-screw granulation and drying process performed on a continuous manufacturing line. During operation, the continuous line logs 49 univariate process variables, hence generating a large amount of data. Three identical 5-h continuous manufacturing runs were performed. Multivariate data analysis tools, more specifically latent variable modeling tools such as principal component analysis, were used to extract information from the generated data sets unveiling process trends and drifts. Furthermore, a statistical process monitoring strategy is presented. The approach is based on the application of multivariate statistical process monitoring to model the variables that remain around a steady state.
International journal of pharmaceutics, Jan 13, 2018
Cocrystals are homogenous (single-phase) crystalline structures composed by two or more component... more Cocrystals are homogenous (single-phase) crystalline structures composed by two or more components in a definite stoichiometric ratio bonded together by noncovalent bonds. Pharmaceutical industry has been showing interest in cocrystals due to their ability to improve active pharmaceutical ingredients (API's) properties, such as solubility, dissolution, bioavailability, stability and processability. The necessity for high-throughput screening methods and methods capable of producing cocrystals in an industrial scale still hinders the use of cocrystals by the pharmaceutical industry. The aim of this review is to present an extensive overview of the cocrystallization methods, focusing in the specificities of each technique, its advantages and disadvantages. The review is divided into solvent-based and solvent-free methods. The most appropriate methods to the different stages of cocrystals manufacture, from the screening phase to industrial production are identified. The use of cont...
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Papers by Mafalda Sarraguça