Caracterização físico-química de efavirenz para o desenvolvimento de sistemas incrementadores de dissolução

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde. Programa de Pós-Graduação em Farmácia.O efavirenz é um antirretroviral pertencente à classe dos inibidores de transcriptase reversa não-análogos de nucleosídeo, é indicado sempre em combinação com outros fármacos e utilizado no tratamento de primeira linha para adultos e crianças. A dose infantil é calculada pelo peso e a dose para adultos é de 600 mg uma vez ao dia. Dado a relevância do problema de solubilidade e biodisponibilidade para tão importante fármaco envolvido em uma questão de saúde pública mundial, o presente trabalho tem como objetivo realizar estudos de pré-formulação para o desenvolvimento de sistemas incrementadores de dissolução. A caracterização de duas matérias-primas (A e B) assegurou tratar-se sempre da mesma forma polimórfica, sendo a empregada pela indústria para formular, e os estudos de compatibilidade entre fármaco e excipientes indicaram ausência de incompatibilidade. Um método por cromatografia líquida de alta eficiência foi otimizado e validado para a quantificação do fármaco pela técnica de dissolução intrínseca. A aplicação do método permitiu identificar entre as matérias-primas a de maior taxa de dissolução, e diferenças significativas foram observadas na taxa de dissolução intrínseca para as matérias-primas previamente caracterizadas e que apresentaram a mesma estrutura cristalina. Os co-processados obtidos por spray-drying e liofilização após processamento em moinho coloidal e co-moagem com 0,2% de hidroxipropilmetilcelulose ou hidroxipropilcelulose e 0,2% de lauril sulfato de sódio apresentaram os melhores perfis de dissolução entre todas as formulações testadas. Quando da associação de lauril sulfato de sódio a qualquer dos dois polímeros derivados de celulose, observou-se entre 80 e 95% de dissolução do fármaco a partir de 5 minutos de análise. Portanto, resultados bastante superiores aos observados para os perfis de dissolução do efavirenz na ausência do surfactante ou de qualquer dos polímeros derivados de celulose foram obtidos. O incremento de dissolução foi alcançado e as perspectivas são de redução de dose e da incidência de reações adversas

Three new hydrochlorothiazide cocrystals: Structural analyses and solubility studies

YesHydrochlorothiazide (HCT) is a diuretic BCS class IV drug with poor aqueous solubility and low permeability leading to poor oral absorption. The present work explores the cocrystallization technique to enhance the aqueous solubility of HCT. Three new cocrystals of HCT with water soluble coformers phenazine (PHEN), 4-dimethylaminopyridine (DMAP) and picolinamide (PICA) were prepared successfully by solution crystallization method and characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), fourier transform –infraredspectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Structural characterization revealed that the cocrystals with PHEN, DMAP and PICA exists in P21/n, P21/c and P21/n space groups, respectively. The improved solubility of HCT-DMAP (4 fold) and HCT-PHEN (1.4 fold) cocrystals whereas decreased solubility of HCT-PICA (0.5 fold) as compared to the free drug were determined after 4 h in phosphate buffer, pH 7.4, at 25 °C by using shaking flask method. HCT-DMAP showed a significant increase in solubility than all previously reported cocrystals of HCT suggest the role of a coformer. The study demonstrates that the selection of coformer could have pronounced impact on the physicochemical properties of HCT and cocrystallization can be a promising approach to improve aqueous solubility of drugs

A SITUAÇÃO EPIDEMIOLÓGICA DA HEPATITE B NO BRASIL

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INCIDÊNCIA DE INFECÇÕES DO TRATO URINÁRIO (ITUS) EM ADOLESCENTES DO SEXO FEMININO DE UMA ESCOLA ESTADUAL NO MUNICÍPIO DE VÁRZEA GRANDE, 2017

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Interaction and compatibility studies of efavirenz with pharmaceutical excipients

Although excipients have traditionally been thought of as being inert, experience has shown that there can be interactions between excipients and drugs. Thus, knowledge of potential physical and chemical interactions can be very useful. The compatibility of efavirenz with the excipients: sodium lauryl sulfate, spray dried lactose, hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose and croscarmellose sodium was studied. X-ray powder diffraction (XRPD), Fourier Transform Infrared Spectroscopy (FT-IR), Raman spectroscopy (RS) and Differential scanning calorimetry (DSC) were used as screening techniques. DSC curves of binary mixtures were quite different from the efavirenz raw material, suggesting a strong interaction, including possible chemical reactions between efavirenz and excipients at increased temperatures. However, FT-IR, XRPD and RS showed that no chemical reaction occurred between efavirenz and excipients at room temperature. Efavirenz can exist in more than one crystalline form, which may have implications for its behavior during production, and also for its in vivo performance. XRPD, DSC, Scanning Electron Microscopy (SEM) and Intrinsic Dissolution Rate (IDR) were used for the solid-state characterization of efavirenz and showed that the raw material used corresponded to Form I and maintained its crystal structure during the study. Intrinsic dissolution studies indicated that bioavailability problems may arise because of the poor solubility of efavirenz

Thermal decomposition kinetics of the antiparkinson drug “entacapone” under isothermal and non-isothermal conditions

© 2017 Akadémiai Kiadó, Budapest, Hungary The thermal decomposition kinetics of entacapone (ENT) have been investigated via thermogravimetric analysis under non-isothermal and isothermal conditions which provide useful stability information for their processing in the pharmaceutical industry and also for predicting shelf life and suitable storage conditions. The determination of the kinetic parameters for the decomposition process under non-isothermal conditions in a nitrogen atmosphere at four heating rates (5, 10, 15, and 20 °C min −1 ) was performed. Kinetic parameters of the decomposition process for ENT were calculated through Friedman, Flynn–Wall–Ozawa, Kissinger–Akahira–Sunose, and Li–Tang methods. This work demonstrates that the activation energies calculated from the decomposition reactions by different methods are consistent with each other. Moreover, the thermodynamic functions of the decomposition reaction were also calculated

Estudo da estrutura cristalina e propriedades de dissolução de fases sólidas de efavirenz e saquinavir, visando a biorrelevância e seu impacto no tratamento do HIV/AIDS

Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmácia, Florianópolis, 2016.As propriedades do estado sólido dos insumos farmacêuticos ativos (IFAs) devem ser compreendidas porque estão diretamente relacionadas ao desempenho dos fármacos. Fármacos pouco solúveis apresentam limitações na biodisponibilidade devido à baixa solubilidade e velocidade de dissolução. Segundo a Organização Mundial da Saúde aproximadamente 40% dos medicamentos administrados por via oral pertencem às Classes II e IV (baixa solubilidade; alta e baixa permeabilidade, respectivamente) do Sistema de Classificação Biofarmacêutica, e, portanto, podem apresentar problemas de biodisponibilidade. O efavirenz (EFV) e o mesilato de saquinavir (SQVM) pertencem a estas classes, são utilizados no tratamento de primeira linha de pacientes portadores do HIV, são fornecidos pelo SUS e por isso são fármacos de interesse da indústria nacional. Neste contexto, o presente trabalho teve por objetivo avaliar a estrutura cristalina, as características do estado sólido e as propriedades de dissolução de fases sólidas de EFV e saquinavir (SQV) visando a biorrelevância e o impacto destes fármacos no tratamento do HIV/ AIDS. Para o EFV, uma forma polimórfica (polimorfo II) dezesseis vezes mais solúvel e termodinamicamente mais estável que a utilizada pela indústria, foi obtida. A caracterização de IFAs de EFV, associada aos resultados do teste de bioequivalência, possibilitou a correlação dos resultados obtidos pelo perfil de dissolução e eficiência de dissolução (DE), com a medida de tamanho de domínio cristalino. Tamanhos de domínio cristalino inferiores a 100 nm forneceram os melhores valores de DE. É provável que exista um tamanho de domínio cristalino ?crítico?, associado a determinado tamanho de partícula, que assegure a bioequivalência dos IFAs. O SQVM cristaliza no sistema monoclínico e grupo espacial P21. O estudo do perfil de dissolução, associado à turbidimetria, e à avalição estrutural do cocristal de SQMV e lauril sulfato de sódio (LSS) obtido, comprovaram ser este surfactante, inapropriado para a avaliação das propriedades de dissolução do fármaco devido à recristalização do SQVM neste meio. Através da avaliação estrutural do cocristal, e com o objetivo de explorar as possibilidades de troca de ânion para o SQVM, três novas formas de SQV foram obtidas com a aplicação da Engenharia de Cristais. Todas foram classificadas como isomorfas do SQVM. A forma de cloridrato, com 38% de fármaco dissolvido em 90 minutos, poderia ser utilizada como alternativa ao mesilato (43%).<br>Abstract : The solid state property of Active Pharmaceutical Ingredients (APIs) should be understood because they are directly related to the performance of drugs. Poorly soluble drugs present limitations in bioavailability due to lower solubility and dissolution rate. According to World Health Organization nearly 40% of orally administrated drugs belong to Class II (poorly soluble, high permeable) and Class IV (poorly soluble, poorly permeable) in the Biopharmaceutical Classification System and, therefore, they may present problems of bioavailability. Efavirenz (EFV) and saquinavir mesylate (SQVM) are drugs which belong to Class II and IV respectively. They are used in the first-line treatment of HIV patients, they are provided by the Public Health System (SUS-Brazil) and thus, they are interesting drugs to national companies. For so, the aim of this work was to evaluate the crystalline structure, the solid state characteristics and the dissolution properties of EFV and SQVM solid phases targeting the biorelevance and the impact of these drugs in the HIV/ AIDS treatment. A polymorphic form of EFV (polymorph II), sixteen times more soluble and thermodynamically more stable than polymorph I (used by industry to formulate), was obtained. The characterization of EFV APIs, correlated with the results from bioequivalence test, allowed the correlation between data from dissolution tests and dissolution efficiency (DE) with the crystalline domain size measures. Crystalline domain size below 100 nm provided the best values of DE. Probably there is a critical crystalline domain size associated with particular particle size, which ensure the bioequivalence of APIs. Concerning the SQVM, it crystallized in the monoclinic system and space group P21. The dissolution profile study, associated with both, turbidimetry and structural analysis of the cocrystal of SQVM and sodium lauryl sulphate (SLS) obtained, confirmed that this surfactant is unsuitable for the evaluation of dissolution properties of this drug. The SQVM recrystallized in that medium. Based on the structural analysis of cocrystal and aiming to explore the possibility of anion-exchange for SQVM, three new forms of SQV were obtained by applying the Crystal Engineering. All the three forms were classified as being isomorphous of SQVM. The hydrochloride form which presented 38% of drug dissolved in 90 minutes could be used as an alternative to mesylate (43%)

Interaction and compatibility studies of efavirenz with pharmaceutical excipients

Although excipients have traditionally been thought of as being inert, experience has showed interaction between them and the drugs; therefore, is very useful the knowledge about potential physical and chemical interactions. The compatibility of efavirenz with the excipients: sodium lauryl sulfate, spray dried lactose, hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose and croscarmellose sodium were studied. X-ray powder diffraction (XRPD), Fourier Transform Infrared Spectroscopy (FT-IR), Raman spectroscopy (RS) and Differential scanning calorimetry (DSC) were used as screening techniques. DSC curves of binary mixtures were quite different than efavirenz raw material, suggesting strong interaction and/ or even chemical reactions between efavirenz and excipients with temperature increasing. However, FT-IR, XRPD and RS showed that no interaction and/ or even chemical reaction between efavirenz and excipients occurred at room temperature. Efavirenz is one non-nucleoside reverse transcriptase inhibitor (NNRTI), used in the High Activity Antiretroviral Therapy (HAART) for the treatment of human immunodeficiency virus type 1 infection (HIV-1). This Active Pharmaceutical Ingredient (API) has more than one crystalline form, which may have implications for its behavior during production and also for its in vivo performance. XRPD, DSC, Scanning Electron Microscopy (SEM) and Intrinsic Dissolution Rate (IDR) were used in the solid-state characterization of efavirenz and was determined that the raw material used corresponds with Form I and maintains its crystal structure during the study. IDR indicated that bioavailability problems may arise because of drug-dependent dissolution

Saquinavir-Piperine Eutectic Mixture: Preparation, Characterization, and Dissolution Profile

The dissolution rate of the anti-HIV drug saquinavir base (SQV), a poorly water-soluble and extremely low absolute bioavailability drug, was improved through a eutectic mixture formation approach. A screening based on a liquid-assisted grinding technique was performed using a 1:1 molar ratio of the drug and the coformers sodium saccharinate, theobromine, nicotinic acid, nicotinamide, vanillin, vanillic acid, and piperine (PIP), followed by differential scanning calorimetry (DSC). Given that SQV-PIP was the only resulting eutectic system from the screening, both the binary phase and the Tammann diagrams were adapted to this system using DSC data of mixtures prepared from 0.1 to 1.0 molar ratios in order to determine the exact eutectic composition. The SQV-PIP system formed a eutectic at a composition of 0.6 and 0.40, respectively. Then, a solid-state characterization through DSC, powder X-ray diffraction (PXRD), including small-angle X-ray scattering (SAXS) measurements to explore the small-angle region in detail, Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and a powder dissolution test were performed. The conventional PXRD analyses suggested that the eutectic mixture did not exhibit structural changes; however, the small-angle region explored through the SAXS instrument revealed a change in the crystal structure of one of their components. FT-IR spectra showed no molecular interaction in the solid state. Finally, the dissolution profile of SQV in the eutectic mixture was different from the dissolution of pure SQV. After 45 min, approximately 55% of the drug in the eutectic mixture was dissolved, while, for pure SQV, 42% dissolved within this time. Hence, this study concludes that the dissolution rate of SQV can be effectively improved through the approach of using PIP as a coformer.Fil: Fandaruff, Cinira. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Tecnologías Emergentes y Ciencias Aplicadas. - Universidad Nacional de San Martin. Instituto de Tecnologías Emergentes y Ciencias Aplicadas; ArgentinaFil: Quirós Fallas, María Isabel. Universidad de Costa Rica; Costa RicaFil: Vega Baudrit, José Roberto. No especifíca;Fil: Navarro Hoyos, Mirtha. Universidad de Costa Rica; Costa RicaFil: Lamas, Diego German. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Instituto de Tecnologias Emergentes y Ciencias Aplicadas. - Universidad Nacional de San Martin. Instituto de Tecnologias Emergentes y Ciencias Aplicadas.; ArgentinaFil: Araya Sibaja, Andrea Mariela. No especifíca