Optimization of the Extraction Conditions of Bioactive Compounds from Ocimum basilicum Leaves Using Ultrasound-Assisted Extraction via a Sonotrode

Sweet basil (Ocimum basilicum) leaves are rich in bioactive compounds that present therapeutic benefits for human health. Ultrasonic-assisted extraction (UAE) is frequently used to obtain phenolic compounds from plants/herbal sources. However, few works have developed multi-variable studies to find the optimal conditions to extract the maximum amount of compounds, especially when applied to UAE via a sonotrode. The purpose of this work was to perform a multi-variable study by employing a Box–Behnken design to collect the highest active compound content from Ocimum basilicum leaves. The efficacy of the design was endorsed by ANOVA. The studied parameters for UAE via a sonotrode were the ethanol/water ratio, amplitude, and time. The analyzed responses were the rosmarinic acid, the sum of phenolic acids, and the sum of phenolic compounds content. The optimal conditions were found to be 50% ethanol/water, 50% amplitude, and 5 min. Twenty bioactive compounds were identified by HPLC-ESI-TOF-MS when the extract was collected by applying the optimal conditions. Ocimum basilicum may be appreciated as a valuable source of important bioactive substances for pharmaceutical use.Fil: Aloisio, Carolina. Universidad Tecnológica Nacional. Facultad Reg.san Francisco. Departamento de Ingeniería Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Razola Díaz, María del Carmen. Universidad de Granada; EspañaFil: Aznar Ramos, María José. Universidad de Granada; EspañaFil: Longhi, Marcela R.. Universidad Nacional de Córdoba; ArgentinaFil: Andreatta, Alfonsina Ester. Universidad Tecnológica Nacional. Facultad Reg.san Francisco. Departamento de Ingeniería Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Verardo, Vito. Universidad de Granada; Españ

Pharmaceutical Systems as a Strategy to Enhance the Stability of Oxytetracycline Hydrochloride Polymorphs in Solution

In order to improve the stability of oxytetracycline hydrochloride, a polymorphic antibiotic set of novel binary systems were developed using β-cyclodextrin and amino acids with different acid-basic characteristics as ligands. The formation constants for each system containing β-cyclodextrin, L-aspartic acid, histidine and N-acetylcysteine were determined by Scott’s method and statistical studies. The structure of the binary systems with β-cyclodextrin and N-acetylcysteine was elucidated by NMR experiments. The effect β-cyclodextrin and N-acetylcysteine on the polymorph’s chemical stability in aqueous and phosphate buffered saline solutions at 25 °C was monitored by an optimized and validated high-performance liquid chromatography method. The combination of N-acetylcysteine with the three polymorphs and the β-cyclodextrin system obtained with the form III demonstrated a reduction in the degradation rate of oxytetracycline hydrochloride in the aqueous solution when compared to each free form, with an increase of 20 h in the half time. It evidences that the use of amino acids as ligands constitutes an interesting alternative for pharmaceutical areas. In conclusion, based on the results obtained, these pharmaceutical systems could be candidates for the development of a pharmaceutical formulation for the administration of the drug through reconstituted solutions using the binary system as a promising tool for improving the stability of oxytetracycline hydrochloride polymorphs in solution

Complexation between darunavir and β-Cyclodextrin. Experimental and theoretical studies

Darunavir (DRV) is a protease inhibitor used in the treatment of HIVinfection, which constitutes a keystone in the therapy of patientsinfected with this virus. Unfortunately, DRV has low solubility inwater and poor bioavailability, therefore it requires administration inrelatively high doses in order to exhibit therapeutic efficacy. Acommonly applied approach to increase the solubility of drugs is theformation of complexes with macromolecules, of which molecularencapsulation with β-cyclodextrin (βCD) constitutes an alternative forthe development of new pharmaceutical dosage forms. Therefore, itwas to evaluate by theoretical (molecular modelling) and experimental(spectroscopic) approaches the possibility of obtaining an inclusioncomplex between DRV and βCD. From the results obtained by thedocking procedures, we found three clusters of conformations for the DRV:β-CD complex, corresponding to conformations in which the ligand moieties were buried into the β-CD hydrophobic cavities. Molecular modelling results were compared with spectroscopic studies, with 1H NMR studies evidencing that DRV and βCD proton resonances were modified upon complexation, thus confirming the formation of the inclusion complex. The combination of theoretical and experimental techniques confirmed the formation of the inclusion complex between DRV and βCD.Fil: Kogawa, A. C.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Zoppi, Ariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Quevedo, Mario Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; ArgentinaFil: Longhi, Marcela Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Nunes Salgado, H. R.. Universidade Estadual Paulista Julio de Mesquita Filho; Brasi

Development and Characterization of Pharmaceutical Systems Containing Rifampicin

Rifampicin is a potent antimicrobial drug with some suboptimal properties, such as poor stability, low solubility, and variable bioavailability. Therefore, in the current study, a multicomponent complex between rifampicin, γ-cyclodextrin, and arginine was prepared with the aim of improving drug properties. Solubility was evaluated by phase-solubility studies. The mechanism of interaction was established through proton nuclear magnetic resonance spectroscopy and molecular modeling. Physicochemical characterization was investigated using Fourier transform-infrared spectroscopy, powder X-ray diffraction, and scanning electron microscopy. The dissolution properties, antimicrobial activity (antibacterial, antibiofilm, and antileishmanial), and stability of the different samples were studied. The results obtained in this investigation demonstrate that multicomponent complexes can improve the water solubility and dissolution rate of rifampicin, as well as its antibacterial and antileishmanial action, and present suitable stability. In conclusion, rifampicin complexed with γ-cyclodextrin and arginine is an attractive approach for developing pharmaceutical dosage forms of rifampicin with increased antimicrobial activities

Furosemide:Triethanolamine Salt as a Strategy To Improve the Biopharmaceutical Properties and Photostability of the Drug

With the purpose of enhancing the biopharmaceutical properties of the furosemide, a pharmaceutical salt was obtained and characterized by combining the drug and triethanolamine. The solid system was prepared using different techniques such as kneading, grinding, and slow evaporation. It was characterizated by X-ray powder diffraction, solid-state nuclear magnetic resonance, infrared and Raman spectroscopy, thermal analysis, and scanning electron microscopy. The results showed that the same pharmaceutical compound in solid state was obtained through the different preparation techniques. The crystalline structure was fully elucidated by single-crystal X-ray diffraction. The salt formation was confirmed by two-dimensional nuclear magnetic resonance experiments, which revealed the transference of the OH proton of the drug to triethanolamine. Besides, the solubility studies demonstrated an increase in the drug solubility attributed not only to a pH change but also to a soluble salt formation in solution. In addition, the combination of the drug with triethanolamine produces an enhancement of the chemical photostability, whereas the physical photostability and the hygroscopicity status were not modified. Finally, this new solid form of furosemide constitutes an interesting strategy to improve the biopharmaceutical properties and stability of furosemide, with potential application in pharmaceutical formulations

Characterization of the Hydrochlorothiazide: β‑Cyclodextrin Inclusion Complex. Experimental and Theoretical Methods

Hydrochlorothiazide (HCT) is one of the most commonly prescribed antihypertensive drugs. In an attempt to gain an insight into the physicochemical and molecular aspects controlling the complex architecture of native β-cyclodextrin (β-CD) with HCT, we performed multiple-temperature–pH isothermal titration calorimetric measurements of the HCT:β-CD system, together with proton nuclear magnetic resonance spectroscopy (¹H NMR), phase solubility analysis, and molecular modeling methods. The A_L-type diagrams, obtained at different pH values and temperatures, suggested the formation of soluble 1:1 inclusion complexes of β-CD with HCT. The corresponding stability constants (<i>K</i>_1:1) were determined by phase solubility studies and compared with those obtained by ITC, with good agreement between these two techniques being found. The three-dimensional array of the complex was studied by ¹H NMR and molecular modeling methods. Both techniques confirmed the formation of the inclusion complex, with good agreement between the experimental and theoretical techniques regarding the HCT binding mode to β-CD. Also, the forces involved in the association process were determined, both from the thermodynamic parameters obtained by ITC (association enthalpy, binding constant, Gibbs free energy, and entropy) and from energetic decomposition analyses derived from computational methods. We concluded that the formation of the HCT:β-CD complex was enthalpy driven, with the inclusion mode of HCT being highly dependent on its ionization state. In all cases, sustained hydrogen bond interactions with hydroxyl groups of β-CD were identified, with the solvation energy limiting the affinity. Regarding the pH and temperature dependence, lower affinity constants were found at higher HCT ionization states and temperatures

Nanostructured lipid carriers as a strategy to improve the in vitro schistosomiasis activity of Praziquantel

Praziquantel (PZQ) is a pyrazinoisoquinoline anthelmintic that was discovered in 1972 by Bayer Germany. Currently, due to its efficacy, PZQ is the drug of choice against all species of Schistosoma. Although widely used, PZQ exhibits low and erratic bioavailability because of its poor water solubility. Nanostructured lipid carriers (NLC), second-generation solid lipid nanoparticles, were developed in the 1990s to improve the bioavailability of poorly water soluble drugs. The aim of this study was to investigate nanostructured lipid carriers as a strategy to improve the efficacy of PZQ in S. mansoni treatment. We prepared NLC2 and NLC4 by adding seventy percent glycerol monostearate (GMS) as the solid lipid, 30% oleic acid (OA) as the liquid lipid and two surfactant systems containing either soybean phosphatidylcholine/poloxamer (PC/P-407) or phosphatidylcholine/Tween 60 (PC/T60), respectively. The carriers were characterized by nuclear magnetic resonance, differential scanning calorimetry, thermogravimetric analysis and Fourier transform-infrared spectroscopy. The safety profile was evaluated using red cell hemolysis and in vitro cytotoxicity assays. The results showed that the encapsulation of PZQ in NLC2 or NLC4 improved the safety profile of the drug. Treatment efficacy was evaluated on the S. mansoni BH strain. PZQ-NLC2 and PZQ-NLC4 demonstrated an improved efficacy in comparison with free PZQ. The results showed that the intestinal transport of free PZQ and PZQ-NLC2 was similar. However, we observed that the concentration of PZQ absorbed was smaller when PZQ was loaded in NLC4. The difference between the amounts of absorbed PZQ could indicate that the presence of T60 in the nanoparticles (NLC4) increased the rigid lipid matrix, prolonging release of the drug. Both systems showed considerable in vitro activity against S. mansoni, suggesting that these systems may be a promising platform for the administration of PZQ for treating schistosomiasis.Fil: Kolenyak Santos, Fernanda. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Garnero, Claudia. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: De Oliveira, Rosimeire N.. Universidade Estadual de Campinas; BrasilFil: De Souza, Ana L. R.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Chorilli, Marlus. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Allegretti, Silmara M.. Universidade Estadual de Campinas; BrasilFil: Longhi, Marcela Raquel. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Chaud, Marco V.. Universidade de Sorocaba; BrasilFil: Gremião, Maria P.D.. Universidade Estadual Paulista Julio de Mesquita Filho; Brasi

Triethanolamine Stabilization of Methotrexate-β-Cyclodextrin Interactions in Ternary Complexes

The interaction of methotrexate (MTX) with beta-cyclodextrin (β-CD) in the presence of triethanolamine (TEA) was investigated with the aim to elucidate the mechanism whereby self-assembly cyclodextrin systems work in association with this third component. Solubility diagram studies showed synergic increment of the MTX solubility to be about thirty-fold. Experiments using 2D ROESY and molecular modeling studies revealed the inclusion of aromatic ring III of the drug into β-CD cavity, in which TEA contributes by intensifying MTX interaction with β-CD and stabilizes MTX:β-CD:TEA ternary complex by electrostatic interaction. The maintenance of these interactions in solid phase was also studied in ternary MTX:β-CD:TEA and comparisons were made with freeze dried binary MTX:β-CD and physical mixtures. FTIR studies evidenced that MTX–β-CD interaction remained in solid ternary complexes, which was also supported by thermal (differential scanning calorimetry (DSC), thermogravimetric analysis (TG)/first derivative of TG analysis (DTG) and C,N,H elementary analysis) and structural (X-ray diffraction analysis, (XRD)) studies, mainly regarding the increment of drug stability. The efficient in vitro drug dissolution studies successfully demonstrated the contribution of ternary complexes, which highlights the importance of this possible new raw material for further applications in drug delivery systemsFil: Barbosa, Jahamunna A.. Universidade Federal do Rio Grande do Norte; BrasilFil: Zoppi, Ariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Quevedo, Mario Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: de Melo, Polyanne. Universidade Federal do Rio Grande do Norte; BrasilFil: de Medeiros, Arthur S. A. Universidade Federal do Rio Grande do Norte; BrasilFil: Streck, Leticia. Universidade Federal do Rio Grande do Norte; BrasilFil: de Oliveira, Alice R.. Universidade Federal do Rio Grande do Norte; BrasilFil: Fernandes Pedrosa, Matheus F.. Universidade Federal do Rio Grande do Norte; BrasilFil: Longhi, Marcela Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: da Silva Junior, Arnobio A.. Universidade Federal do Rio Grande do Norte; Brasi