Browsing by Author "Reis, Salette"
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- Acid/Base Properties of β-Blockers and Benzodiazepines in Sodium Dodecyl Sulfate Micelles. A Spectrophotometric and Potentiometric StudyPublication . de Castro, Baltazar; Gameiro, Paula; Guimarães, Carla; Lima, José L.F.C.; Reis, SaletteThe effect of sodium dodecyl sulfate (SDS) micelles on the acid-base properties of two family of pharmaceutical drugs (beta-blockers and benzodiazepines) at 25 degrees C and I = 0.1 M NaCl have been studied. The characterization of the several solution equilibria for the system drug/SDS micelle solution was performed by potentiometry and spectrophotometry, below and above the critical micelle concentration (cmc). Two widely used models have been applied to quantify the effect of micelles on the pKa of the drugs, and the results obtained point to different interactions of each family of drugs with the micelles.
- Fluorimetric and solubility studies of nadolol and atenolol in SDS micellesPublication . de Castro, Baltazar; Gameiro, Paula; Guimarães, Carla; Lima, José L.F.C; Reis, SaletteThe effect of sodium dodecyl sulfate (SDS) micelles on the spectrofluorimetric intensities and on the solubility of two b-blockers (atenolol and nadolol) were studied at 25.090.1°C and I=0.1 M NaCl. From the dependence of these physical properties on SDS concentration it was possible to calculate the binding constants drug-micelle, and it was found that both techniques yield similar results for the binding constants, and that are in agreement with those calculated from the effect of micelles on the apparent acidity constants of the b-blockers.
- Noninvasive methods to determine the critical micelle concentration of some bile acid saltsPublication . Reis, Salette; Moutinho, Carla Guimarães; Matos, Carla; de Castro, Baltazar; Gameiro, Paula; Lima, José L.F.C.In this work the critical micelle concentrations (cmc) of four bile salts, sodium cholate, sodium glycocholate, sodium deoxycholate, and sodium glycodeoxycholate, are determined and presented. Three independent noninvasive methodologies (potentiometry, derivative spectrophotometry, and light scattering) were used for cmc determination, at 25 degrees C with ionic strength adjusted to 0.10 M with NaCl. Spectrophotometric and potentiometric studies of some bile salts were also executed at various ionic strength values, thus allowing the influence of the ionic strength on the cmc value of the bile salt to be assessed. A critical comparison of the cmc values obtained with data collected from the literature is presented. Furthermore, this work makes an evaluation of the conceptual bases of different methodologies commonly used for cmc determination, since variations in the results obtained can be related mainly to different intrinsic features of the methods used (such as sensitivity or the need to include tracers or probes) or to the operational cmc definition applied. The undoubted definition of the experimental bile salt concentration that corresponds to cmc (operational cmc) is essential since in the case of these amphiphiles the formation of micelles is not as abrupt as in the case of ordinary association colloids. The biphasic nature of their aggregation leads to a "round-shaped" variation of the experimental parameters under analysis, which makes difficult the evaluation of the cmc values and can be responsible for the different results obtained.
- Partition coefficients of β-blockers in bile salt/lecithin micelles as a tool to assess the role of mixed micelles in gastrointestinal absorptionPublication . de Castro, Baltazar; Gameiro, Paula; Guimarães, Carla; Lima, José L.F.C; Reis, SaletteThe objective of this study was to develop non-invasive spectroscopic methods to quantify the partition coefficients of two β-blockers, atenolol and nadolol, in aqueous solutions of bile salt micelles and to assess the effect of lecithin on the partition coefficients of amphiphilic drugs in mixed bile salt/lecithin micelles, which were used as a simple model for the naturally occurring mixed micelles in the gastrointestinal tract. The partition coefficients (Kp) at 25.0±0.1°C and at 0.1 M NaCl ionic strength were determined by spectrofluorimetry and by derivative spectrophotometry, by fitting equations that relate molar extinction coefficients and relative fluorescence intensities to the partition constant Kp. Drug partition was controlled by the: (i) drug properties, with the more soluble drug in water (atenolol) exhibiting smaller values of Kp, and with both drugs interacting more extensively in the protonated form; and by (ii) the bile salt monomers, with the dihydroxylic salts producing larger values of Kp for the β-blockers, and with glycine conjugation of the bile acid increasing the values of Kp for the β-blockers. Addition of lecithin to bile salt micelles decreases the values of Kp of the β-blockers. Mixed micelles incorporate hydrophobic compounds due to their large size and the fluidity of their core, but amphiphilic drugs, for which the interactions are predominantly polar/electrostatic, are poorly incorporated in mixed micelles of bile salts/lecithin.
- Phenolic acids and derivatives: studies on the relationship among structure, radical scavenging activity, and physicochemical parametersPublication . Silva, Francisco A. M.; Borges, Fernanda; Guimarães, Carla; Lima, José L. F. C.; Matos, Carla; Reis, SaletteThe antiradical activity of caffeic acid (1), dihydrocaffeic acid (5), and their corresponding n-alkyl esters was evaluated by using the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH(*)) method. Dihydrocaffeic acid (5) was the most potent compound, having an antiradical effect higher than that of (+/-)-alpha-tocopherol, whereas caffeic acid (1) was less efficient. Esterification of the carboxyl group of dihydrocaffeic acid (5) had a dramatic effect on its antiradical potency, but similar effects were not observed for caffeic acid (1) derivatives. The n-alkyl esters of both phenolic series had similar potencies, and their antiradical activities were independent of the alkyl chain length. Dose-dependent scavenger effects were found in both series. Acid-base properties of the compounds, evaluated by using potentiometry and spectrophotometry, showed that the catechol moiety had pK(a2) and pK(a3) values of 9. 24-9.02 and 11.38-10.99 in the dihydrocaffeic series and 8.48-8.24 and 11.38-11.07 in the caffeic series, respectively. Antiradical activity and pK(a) values of the compounds were not related.
- Potentiometric studies on the complexation of copper(II) by phenolic acids as discrete ligand models of humic substancesPublication . Borges, Fernanda; Guimarães, Carla; Lima, Jose L.F.C.; Pinto, Isabel; Reis, SaletteStudies on the complexation of copper(II) by phenolic acids, as ligand models of humic substances were done by potentiometry. The acids under study were: 3,4-dihydroxyhydrocinnamic acid or hydrocaffeic acid (1), 3,4-dihydroxyphenylacetic acid (2) and 3,4-dihydroxybenzoic acid or protocatechuic acid (3). Acidity constants of the ligands and the formation constants of metal-ligand complexes were evaluated by computer programs. The carboxylic group of the phenolic acids has different pK(a1) values, being the dissociation constants intrinsically related with the distance between the function and the aromatic nucleus. The results obtained allow concluding that acidity constants of the catechol moiety of the compounds are similar with pK(a2) and pK(a3) values between 9.47-9.41 and 11.55-11.70. The complexation properties of the three ligands towards copper(II) ion are quite similar, being the species found not different either in nature or stability. Although the model ligands have some structural differences no significant differences were found in their complexation properties towards copper(II). So, it can be postulated that complexation process is intrinsically related with the presence of a catechol group.
- Study of partition of nitrazepam in bile salt micelles and the role of lecithinPublication . de Castro, Baltazar; Gameiro, Paula; Guimarães, Carla; Lima, José L.F.C; Reis, SaletteThe effect of trihydroxy (sodium cholate and sodium glycocholate) and dihydroxy (sodium deoxycholate and sodium glycodeoxycholate) bile salt micelles on the spectrophotometric properties and on the solubility of nitrazepam in aqueous solution, at 25.0°C and at ionic strength 0.1 M in sodium chloride, has been assessed. From the results obtained it was possible to calculate the partition coefficients (Kp) of nitrazepam between aqueous and micellar phases. The partition coefficients of nitrazepam have also been determined in mixed micelles of cholate or deoxycholate with lecithin (egg yolk phosphatidylcholine), which were used as a model of the gastrointestinal tract. Drug partition was found to depend on the bile acid (number of hydroxyl groups and conjugation with glycine), and our data indicate further that addition of lecithin to bile salt micelles decreases the values of the partition coefficients in the mixed micelles at physiological pH.
- β-Blockers and benzodiazepines location in SDS and bile salt micellar systemsPublication . Reis, Salette; Moutinho, Carla Guimarães; Pereira, Eulália; de Castro, Baltazar; Gameiro, Paula; Lima, José L.F.C.The work here described aimed to find out the location of the different species of two families of pharmaceutical substances, namely two beta-blockers (atenolol and nadolol) and two benzodiazepines (midazolam and nitrazepam) in synthetic (sodium dodecyl sulphate, SDS) and natural (bile salts-sodium cholate and sodium deoxycholate) micellar aggregate solutions. Electronic spin resonance spectroscopy studies were carried out, at 25 degrees C and at an ionic strength of 0.10 M in NaCl, using 5-, 12- and 16-doxylstearic acid probes (AS). The immobilization degree of solubilized stearic acid spin probes was found to vary with the position of the nitroxide group in the sequence 5-doxylstearic acid>12-doxylstearic acid>16-doxylstearic acid for SDS and 12-doxylstearic acid>5-doxylstearic acid>16-doxylstearic acid for both bile salts investigated. Therefore, from the rotational correlational time values obtained, it can be inferred that the structure of bile salt micelles is markedly different from that of SDS micelles and the results suggest that the bile salt micelles studied have similar structure independently of differences in the molecular structure of the respective bile salts. Drug location studies were performed at pH 4.0 (SDS solutions) or 7.0 (bile salt solutions) and 10.8 in order to study the effect of the drug ionisation on its relative position on micelles. The results have shown that drug location is controlled by the (i) drug hydrophilicity and acid/base properties, with the more soluble compound in water (atenolol) exhibiting smaller variation of rotational correlational time (in SDS and bile salts solutions), and with both beta-blockers exhibiting smaller deviations in the protonated forms and (ii) the bile salt monomers, with the dihydroxylic bile salt (deoxycholate) producing larger differences. The work described herein allow us to conclude that the (protonated) beta-blockers are probably located on the surface of the detergent micelles, and linked to them by means of essentially electrostatic forces, while the (neutral) benzodiazepines are probably located deeper in the interior of the micelles.