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

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

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%)

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

Irbesartan desmotropes: Solid-state characterization, thermodynamic study and dissolution properties

Documento OriginalIrbesartan (IBS) is a tetrazole derivative and antihypertensive drug that has two interconvertible structures, 1H- and 2H-tautomers. The difference between them lies in the protonation of the tetrazole ring. In the solid-state, both tautomers can be isolated as crystal forms A (1H-tautomer) and B (2H-tautomer). Studies have reported that IBS is a polymorphic system and its forms A and B are related monotropically. These reports indicate form B as the most stable and less soluble form. Therefore, the goal of this contribution is to demonstrate through a complete solid-state characterization, thermodynamic study and dissolution properties that the IBS forms are desmotropes that are not related monotropically. However, the intention is also to call attention to the importance of conducting strict chemical and in solid-state quality controls on the IBS raw materials. Hence, powder X-ray diffraction (PXRD) and Raman spectroscopy (RS) at ambient and non-ambient conditions, differential scanning calorimetry (DSC), hot stage microscopy (HSM), Fourier transform infrared (FT-IR) and scanning electron microscopy (SEM) techniques were applied. Furthermore, intrinsic dissolution rate (IDR) and structural stability studies at 98% relative humidity (RH), 25 °C and 40 °C were conducted as well. The results show that in fact, form A is approximately four-fold more soluble than form B. In addition, both IBS forms are stable at ambient conditions. Nevertheless, structural and/or chemical instability was observed in form B at 40 °C and 98% RH. IBS has been confirmed as a desmotropic system rather than a polymorphic one. Consequently, forms A and B are not related monotropically. © 2019 Xi'an Jiaotong UniversityIrbesartan (IBS) es un derivado del tetrazol y un fármaco antihipertensivo que tiene dos estructuras interconvertibles, tautómeros 1H y 2H. La diferencia entre ellos radica en la protonación del anillo de tetrazol. En estado sólido, ambos tautómeros pueden aislarse como formas cristalinas A (tautómero 1H) y B (tautómero 2H). Los estudios han informado que IBS es un sistema polimórfico y sus formas A y B están relacionadas monotrópicamente. Estos informes indican que la forma B es la forma más estable y menos soluble. Por lo tanto, el objetivo de esta contribución es demostrar a través de una caracterización completa del estado sólido, el estudio termodinámico y las propiedades de disolución que las formas de IBS son desmótropos que no están relacionados monotrópicamente. Sin embargo, la intención también es llamar la atención sobre la importancia de llevar a cabo controles estrictos de calidad química y en estado sólido en las materias primas de IBS. Por lo tanto, difracción de rayos X en polvo (PXRD) y espectroscopía Raman (RS) en condiciones ambientales y no ambientales, calorimetría de barrido diferencial (DSC), microscopía de etapa caliente (HSM), infrarroja por transformada de Fourier (FT-IR) y microscopía electrónica de barrido. Se aplicaron técnicas (SEM). Además, también se realizaron estudios de tasa de disolución intrínseca (IDR) y estabilidad estructural a 98% de humedad relativa (RH), 25 ° C y 40 ° C. Los resultados muestran que, de hecho, la forma A es aproximadamente cuatro veces más soluble que la forma B. Además, ambas formas de IBS son estables en condiciones ambientales. Sin embargo, se observó inestabilidad estructural y / o química en la forma B a 40 ° C y 98% de HR. Se ha confirmado que el IBS es un sistema desmotrópico en lugar de polimórfico. En consecuencia, las formas A y B no están relacionadas monotrópicamente.Laboratorio Nacional de Nanotecnología LANOTEC-CeNAT-CONAREEscuela de Ciencia e Ingeniería de los MaterialesTecnológico de Costa Rica, CartagoEscuela de Química, Universidad de Costa Rica, San Pedro de Montes de Oca, San José, Costa RicaPrograma de Pós-Graduação em Física, Universidade Federal de Santa Catarina, Florianópolis, BrazilIndependent Researcher, Barueri, São Paulo, 06472-005, Brazil; Laboratorio de Investigación y Tecnología de Polímeros POLIUNAUniversidad Nacional, Costa RicaEscuela de Químic

Grinding effect on levofloxacin hemihydrate

The grinding techniques were used in different pharmacotechnical process. the control of the effect of grinding in solid state properties of drugs is very important, mainly in hydrated drugs. Levofloxacin hemihydrate (LVF) is a good example of this type of compounds and a broad spectrum antibiotic of the fluoroquinolone drug class. the samples of LVF with and without grinding were studied using different characterization techniques such as thermogravimetry, differential scanning calorimetry, fourier-transformed infrared, X-ray powder diffraction, and hot stage microscopy. the purpose of the present study was to evaluate the effects of grinding in the dehydration and rehydration processes in levofloxacin hemihydrate. After heating, the samples lost water molecules and the rehydration process was modified depending on defects due to the grinding. At room temperature, the complete transformation to the hemihydrate form was detected only for the sample without grinding. On the other hand, the milled sample showed two phases, hydrate and anhydrate forms. Therefore, the defects in the crystalline structure would cause the irreversible transformation.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Univ Fed Santa Catarina, PGFAR, BR-88040970 Florianopolis, SC, BrazilNatl Univ Cordoba, Fac Math Astron & Phys FAMAF, Cordoba, ArgentinaUniv Fed Santa Catarina, BR-88040970 Florianopolis, SC, BrazilUniversidade Federal de São Paulo, Inst Ciencia & Tecnol, São Paulo, BrazilUniversidade Federal de São Paulo, Inst Ciencia & Tecnol, São Paulo, BrazilWeb of Scienc

Isomorphous Salts of Anti-HIV Saquinavir Mesylate: Exploring the Effect of Anion-Exchange on Its Solid-State and Dissolution Properties

Saquinavir (SQV) is an important protease inhibitor used for AIDS/HIV antiretroviral therapy. As a free base it is almost insoluble in water, and it is commercialized as its mesylate salt (SQVM), classified as belonging to class IV (low permeability and solubility). Anion exchange has been used in this work to explore the effect of halides replacing the mesylate anion on the solid state and solubility properties of saquinavir at ambient temperature. All solid forms obtained were characterized via X-ray single crystal and powder diffraction, and their thermal behavior was analyzed via differential scanning calorimetry, thermogravimetric analysis, hot-stage microscopy and variable temperature X-ray powder diffraction. Saquinavir chloride (SQVCl), saquinavir bromide (SQVBr), and saquinavir iodide (SQVI) are all hydrates, the difference in the anion size being responsible for the different number of water molecules (3, 2, and 1, respectively). Dissolution properties have also been investigated, and it has been found that the behavior in water of SQVM and SQVCl are very similar, with 43 and 38% dissolved in 90 min, respectively, whereas for SQVBr and SQVI this percentage was 31 and 18%, respectively. Solid SQVCl could therefore be used as a valid alternative to current pharmaceutical formulations

Crystal Forms of the Antihypertensive Drug Irbesartan: A Crystallographic, Spectroscopic, and Hirshfeld Surface Analysis Investigation.

The design of new pharmaceutical solids with improved physical and chemical properties can be reached through in-detail knowledge of the noncovalent intermolecular interactions between the molecules in the context of crystal packing. Although crystallization from solutions is well-known for obtaining new solids, the effect of some variables on crystallization is not yet thoroughly understood. Among these variables, solvents are noteworthy. In this context, the present study aimed to investigate the effect of ethanol (EtOH), acetonitrile (MeCN), and acetone (ACTN) on obtaining irbesartan (IBS) crystal forms with 2,3-dibromosuccinic acid. Crystal structures were solved by single-crystal diffraction, and the intermolecular interactions were analyzed using the Hirshfeld surfaces analysis. The characterization of physicochemical properties was carried out by powder X-ray diffraction, Fourier transform infrared spectroscopy (FT-IR), thermal analysis, and solution-state NMR techniques. Two different IBS salts were obtained, one from MeCN and ACTN (compound 1) and a different one from EtOH (compound 2). The experimental results were in agreement with the findings obtained through quantum mechanics continuum solvation models. Compound 1 crystallized as a monoclinic system P21/c, whereas compound 2 in a triclinic system P1̅. In both structures, a net of strong hydrogen bonds is present, and their existence was confirmed by the FT-IR results. In addition, the IBS cation acts as a H-bond donor through the N1 and N6 nitrogen atoms which interact with the bromide anion and the water molecule O1W in compound 1. Meanwhile, N1 and N6 nitrogen atoms interact with the oxygen atoms provided by two symmetry-related 2,3-dibromo succinate anions in compound 2. Solution-state NMR data agreed with the protonation of the imidazolone ring in the crystal structure of compound 1. Both salts presented a different thermal behavior not only in melting temperature but also in thermal stability