Sílvia Storpirtis

Thermal analysis of the antiretroviral zidovudine (AZT) and evaluation of the compatibility with excipients used in solid dosage forms.

Modern thermal analysis techniques are frequently used because of their ability to provide detailed information about both the physical and the energetic properties of a substance. In the present work, the thermal decomposition of zidovudine (AZT) was studied using differential scanning calorimetry (DSC) and thermogravimetry/derivative thermogravimetry (TG/DTG). Thermal analysis was supplemented using elemental analysis (C, H, and N), infrared (IR) spectroscopy, and X-ray powder diffraction to characterize the solid intermediates products. Volatile products of the thermal decomposition of AZT were studied by a system composed of the TG/DTA coupled gas chromatography/mass spectrometry (GC/MS). The physical-chemical properties and compatibilities of several commonly used pharmaceutical excipients with AZT were evaluated using thermal methods. The results showed that the product originated from the first thermal decomposition stage corresponds to the cleavage followed by elimination of the azide group and consequent formation of thymine. The second event corresponds to thermal decomposition of thymine. TG/DTA-GC/MS system identified thymines decomposition products as furan and 2-furanmethanol like volatile species. Comparison of the thermoanalytical profiles of the mixtures with individual compounds did not give any evidence of interactions.

Comparison of bidirectional lamivudine and zidovudine transport using MDCK, MDCK–MDR1, and Caco-2 cell monolayers

Bidirectional transport studies were conducted using Caco-2, MDCK, and MDCK-MDR1 to determine P-gp influences in lamivudine and zidovudine permeability and evaluate if zidovudine permeability changes with the increase of zidovudine concentration and/or by association of lamivudine. Transport of lamivudine and zidovudine separated and coadministrated across monolayers based on these cells were quantified using LC-MS-MS. Drug efflux by P-gp was inhibited using GG918. Bidirectional transport of lamivudine and zidovudine was performed across MDCK-MDR1 and Caco-2 cells. Statistically significant transport decrease in B --> A direction was observed using MDCK-MDR1 for zidovudine and MDCK-MDR1 and Caco-2 for lamivudine. Results show increased transport in B --> A and A --> B directions as concentration increases but data from P(app) increase in both directions for both drugs in Caco-2, decrease in MDCK, and does not change significantly in MDCK-MDR1. Zidovudine transport in A --> B direction increases when coadministrated with increasing lamivudine concentration but does not change significantly in B --> A direction. Zidovudine and lamivudine are P-gp substrates, but results assume that P-gp does not affect significantly lamivudine and zidovudine. Their transport in monolayers based on Caco-2 cells increase proportionally to concentration (in both directions) and zidovudine transport in Caco-2 cell monolayer does not show significant changes with lamivudine increasing concentrations.

A importância e a história dos estudos de utilização de medicamentos

No mundo atual, onde ha ampla necessidade de racionalizacao de recursos, sobretudo nos paises mais pobres, esses estudos apresentam-se como alternativa que permite reduzir custos sem perda de qualidade nos tratamentos medicos, alem de terem como funcao detectar possiveis abusos no uso dos medicamentos ou a ocorrencia de eventos adversos. Os medicamentos representam boa parcela dos gastos publicos com saude e nao sao substâncias inocuas. Essas sao as duas principais razoes pelas quais, cada vez mais, se reconhece a necessidade e a importância dos estudos que analisam os tratamentos medicamentosos, em especial nos hospitais, e os dados relativos ao consumo em si. Os ultimos possibilitam a aplicacao da farmacoeconomia e da farmacoepidemiologia como ferramentas no combate a utilizacao inadequada de medicamentos e a gastos desnecessarios. A pesquisa tornou possivel confirmar a importância da ocorrencia desses estudos, especialmente em hospitais, visando a reducao do gasto com medicamentos. A deteccao de desvios, ineficacia e eventos adversos com a utilizacao inadequada de medicamentos possibilita, em nivel macro, o desenvolvimento de politicas governamentais e, em nivel micro, a realizacao de intervencoes educativas - ambas as medidas tendo como objetivo a utilizacao dos medicamentos de forma racional.

Synthesis and photophysical study of highly luminescent coordination compounds of rare earth ions with thenoyltrifluoroacetonate and AZT.

This work presents the study of the interaction between zidovudine (AZT) and rare earth (RE) ions with thenoyltrifluoroacetonate (TTA). The complexes [RE(TTA)(3) x (AZT)(2)] (where RE(III)=Eu and Gd) were prepared by reaction between the [RE(TTA)(3) x (H(2)O)(2)] precursors and AZT dissolved in acetone in the molar ratio 1:2. The obtained luminescent materials were characterized by microanalyses (C, H, N), complexometric titration, IR spectroscopy, X-ray powder diffraction and thermal analysis (DSC and TG/DTG). The luminescence data indicate that the substitution of the two water molecules by AZT in the europium complex causes an intensification of luminescence corresponding to the (5)D(0) -->(7)F(J) (J=0-4) transitions associated with one of the site symmetries. Based on the luminescence spectrum of the Eu(III)-compound the Omega(lambda) experimental intensity parameters (lambda=2 and 4) were calculated for the electronic transitions (5)D(0)-->(7)F(2, 4). The Omega(2) intensity parameter for this new compound is higher than for the precursor compound, suggesting an effective interaction between the AZT and the chemical environment of the Eu(III) ion. Luminescence data confirm that the AZT complex and precursor compound have a comparable emission quantum efficiency.

In vitro evaluation of dissolution properties and degradation products of omeprazole in enteric-coated pellets.

This report describes results of an in vitro study in which capsules containing omeprazole in enteric-coated pellets from different Brazilian manufacturers were evaluated. The original product was the reference in comparison to three similar products (A, B, and C). Samples were submitted to severe conditions (40 degrees C and 75% relative humidity during 120 days), and the tests performed were the omeprazole content, the percentage of omeprazole dissolved from the pellets, and the amount of H 238/85, its main degradation product. The data obtained suggest that these products could not be considered interchangeable. Differences in physical and physicochemical properties of products A, B, and C indicated that they did not maintain the required stability and that bioavailability might be affected by the poor dissolution of omeprazole from the pellets.

Modelos in vitro para determinação da absorção de fármacos e previsão da relação dissolução/absorção

Farmacos contidos em formas farmaceuticas solidas devem ter adequada solubilidade aquosa e permeabilidade intestinal para serem absorvidos apos administracao oral. A velocidade e a extensao com as quais um farmaco e absorvido podem variar devido as suas caracteristicas fisico-quimicas e fatores relacionados a desintegracao e dissolucao. Segundo o Sistema de Classificacao Biofarmaceutica (SCB), a dissolucao e a permeacao intestinal do farmaco podem limitar a absorcao e, consequentemente, a acao terapeutica. Este trabalho objetiva discutir dados da literatura referentes a previsao da relacao entre a dissolucao de farmacos e sua absorcao empregando sistemas in vitro. Para avaliar a permeacao in vitro sao discutidos modelos com tecidos e segmentos intestinais, vesiculas extraidas de membranas e cultura de celulas. Na literatura existem estudos de permeabilidade utilizando celulas Caco-2, TC-7, 2/4/A1, MDCK e MDCK-MDR1. As celulas Caco-2 sao extraidas de adenocarcinoma de colon humano que, em cultura celular, se diferenciam em enterocitos, podendo ser acopladas a sistemas de dissolucao. Estas tecnicas representam importante ferramenta para estudos de dissolucao/permeacao, porem, ainda sao limitadas e nao conseguem reproduzir adequadamente os mecanismos de transporte ativo.

A comparative analysis of biopharmaceutics classification system and biopharmaceutics drug disposition classification system: A cross-sectional survey with 500 bioequivalence studies†

Although policies of waiving bioequivalence studies are part of the legal framework of various regulatory agencies, there is no harmonization with regard to extension of the biowaiver to drugs other than those with high solubility and high permeability, nor is there any consensus or official endorsement of the biopharmaceutics drug disposition classification system (BDDCS). To better understand the applicability of the biowaiver, we carried out a cross-sectional survey to estimate the relative risk of obtaining nonbioequivalent (non-BE) or bioinequivalent (BIE) results for drug products containing drugs belonging to each of the biopharmaceutics classification system (BCS) and BDDCS classes. Five hundred bioequivalence studies were randomly sampled from a database of the Brazilian Health Surveillance Agency (ANVISA). The drugs were classified according to the BCS and BDDCS, to evaluate how characteristics related to drug and dosage form influence the outcome of bioequivalence studies. The relative risk of obtaining a non-BE result was approximately four times lower for drugs in classes 1 and 3 of BCS or BDDCS when compared with class 2 drugs. Thus, it seems that the final outcome of a bioequivalence study is strongly influenced by the solubility of the drug, but not by its intestinal permeability or extent of metabolism.

Thermal behavior and decomposition kinetics of rifampicin polymorphs under isothermal and non-isothermal conditions

The thermal behavior of two polymorphic forms of rifampicin was studied by DSC and TG/DTG. The thermoanalytical results clearly showed the differences between the two crystalline forms. Polymorph I was the most thermally stable form, the DSC curve showed no fusion for this species and the thermal decomposition process occurred around 245 oC. The DSC curve of polymorph II showed two consecutive events, an endothermic event (Tpeak = 193.9 oC) and one exothermic event (Tpeak = 209.4 oC), due to a melting process followed by recrystallization, which was attributed to the conversion of form II to form I. Isothermal and non-isothermal thermogravimetric methods were used to determine the kinetic parameters of the thermal decomposition process. For non-isothermal experiments, the activation energy (Ea) was derived from the plot of Log β vs 1/T, yielding values for polymorph form I and II of 154 and 123 kJ mol-1, respectively. In the isothermal experiments, the Ea was obtained from the plot of lnt vs 1/T at a constant conversion level. The mean values found for form I and form II were 137 and 144 kJ mol-1, respectively.

Determinação dos teores de umidade e cinzas de amostras comerciais de guaraná utilizando métodos convencionais e análise térmica

Paullinia cupana Kunth a vegetable popularly known as guarana, belongs to the Sapindaceas plant family and is predominant in the Amazon region. The low quality of this product can be attributed to the species and less noble varieties, harvest techniques and/or inadequate processing or, yet due to addition of substances that are not included in its natural composition. The main goal of this work was to evaluate from thermogravimetry (TG)/derivative thermogravimetry (DTG) and differential scanning calorimetry (DSC), the thermal behavior of powdered guarana samples in the Brazilian market in order to evaluate the thermal behavior of guarana powder samples commercialized in Brazil and to establish a comparative study between conventional and TG methods for humidity contents determination and ashes. In general, the samples did not present significant differences in the DSC curves profiles and TG/DTG. The thermogravimetry showed that it is possible to decrease the time of the analysis using less amount of sample and allowed to determine humidity and ashes contents. In relation to conventional method the errors of analysis inherent of the samples manipulation were decreased. The thermoanalytical techniques have shown potential applications in the determination of technological parameters, such as: quality control, toasting and adequate stock conditions.

Design, synthesis and biological evaluation of hybrid bioisoster derivatives of N-acylhydrazone and furoxan groups with potential and selective anti-Trypanosoma cruzi activity

Hybrid bioisoster derivatives from N-acylhydrazones and furoxan groups were designed with the objective of obtaining at least a dual mechanism of action: cruzain inhibition and nitric oxide (NO) releasing activity. Fifteen designed compounds were synthesized varying the substitution in N-acylhydrazone and in furoxan group as well. They had its anti-Trypanosoma cruzi activity in amastigotes forms, NO releasing potential and inhibitory cruzain activity evaluated. The two most active compounds (6, 14) both in the parasite amastigotes and in the enzyme contain the nitro group in para position of the aromatic ring. The permeability screening in Caco-2 cell and cytotoxicity assay in human cells were performed for those most active compounds and both showed to be less cytotoxic than the reference drug, benznidazole. Compound 6 was the most promising, since besides activity it showed good permeability and selectivity index, higher than the reference drug. Thereby the compound 6 was considered as a possible candidate for additional studies.