Molecular structures of two copper complexes with the pharmaceuticals norfloxacin and tinidazole, when powder X-ray diffraction assists multi-domain single-crystal X-ray diffraction.

The crystal structures of bis[1-ethyl-6-fluoro-4-oxo-7-(piperazin-1-ium-4-yl)-1,4-dihydroquinoline-3-carboxylato]copper(II) sulfate heptahydrate, [Cu(C16H18FN3O3)2]SO4·7H2O or [Cu(nor)2]SO4·7H2O (nor is norfloxacin), and bis{1-[2-(ethylsulfonyl)ethyl]-2-methyl-5-nitroimide}dinitratocopper(II), [Cu(NO3)2(C8H13N3O4S)2] or [Cu(NO3)2(tnz)2] (tnz is tinidazole), were solved by X-ray diffraction. Both complexes crystallize in the space group P21/c, with Z = 4 (for nor) and Z = 2 (for ntz) molecules per unit cell. In [Cu(nor)2]SO4·7H2O, the CuII ion is at the centre of a square-planar environment, trans coordinated to two independent norfloxacin molecules in the zwitterionic form acting as bidentate ligands through one of the carboxyl (cbx) and the carbonyl (cb) O atoms. The solid is further stabilized by an extensive network of N-H...O(sulfate), N-H...O(cbx), N-H...OW, OW-H...O(sulfate) and OW-H...OW hydrogen bonds. The [Cu(NO3)2(tnz)2] complex is centrosymmetric, with the CuII ion in a square planar environment, coordinated to a tinidazole molecule acting as a monodentate ligand through its imidazole N atom and to one nitrate O atom. The vibrational FT-IR absorption spectra and thermal behaviour of the complexes were also studied and are briefly discussed based on the crystal structures.

Incorporación de un novedoso complejo de tinidazol con propiedades antimicrobianas a dos formas semisólidas de uso tópico / Incorporation of a novel tinidazole complex with antimicrobial properties into two semi-solid topical forms / Incorporação de um novo complexo de tinidazol com propriedades antimicrobianas a duas formas semissólidas para uso tópico

RESUMEN Introducción: El aumento de la resistencia bacteriana a los antibióticos comúnmente empleados para el tratamiento de infecciones cutáneas pone en manifiesto la necesidad de encontrar medicamentos alternativos y eficaces, capaces de contrarrestar este problema de salud que no sólo implica una región, sino que se ha convertido en un problema de salud mundial. Se ha demostrado que un novedoso complejo a base de tinidazol y cobre ([Cu(tnz)2(NO3)2]) posee buena actividad antimicrobiana, sin embargo, para que pueda emplearse como una alternativa para el uso tópico, debe poseer las características necesarias para incorporarse en una formulación que permita su aplicación. Objetivo: Las formas farmacéuticas semisólidas constituyen el grupo más empleado dentro de las formulaciones dermatológicas; se elaboraron dos tipos formulaciones una tipo crema y otra crema-gel, con el fin de verificar en cuál de ellas incorpora convenientemente el complejo [Cu(tnz)2(NO3)2]. Para ambas formulaciones se determinaron las propiedades organolépticas, pH, área de extensibilidad, viscosidad, y tamaño de partícula del complejo. Resultados: Obtenidos evidencian las ventajas de la formulación tipo crema frente a la crema-gel.

SUMMARY Introduction: The increase in bacterial resistance to antibiotics commonly used for the treatment of skin infections highlights the need to find alternative and effective drugs, capable of counteracting this health problem that not only involves a region but has become into a global health problem. A novel complex based on tinidazole and copper ([Cu(tnz)2(NO3)2]) has been shown to have good antimicrobial activity, however, in order to be used as an alternative for topical use, it must have the characteristics necessary to be incorporated into a formulation that allows its application. Aim: Semi-solid pharmaceutical forms are the most widely used group within dermatological formulations; Two types of formulations were elaborated, one type of cream and the other cream-gel, in order to verify in which of them the complex [Cu(tnz)2(NO3)2] is conveniently incorporated. For both formulations, the organoleptic properties, pH, area of extensibility, viscosity, and particle size of the complex were determined. Results: Obtained show the advantages of the cream-type formulation compared to the cream-gel.

RESUMO Introdução: O aumento da resistência bacteriana aos antibióticos comumente utilizados no tratamento de infecções cutâneas evidencia a necessidade de encontrar medicamentos alternativos e eficazes, capazes de fazer frente a esse problema de saúde que não envolve apenas uma região, mas se tornou um problema de saúde global. Um novo complexo à base de tinidazol e cobre ([Cu(tnz)2(NO3)2]) demonstrou ter boa atividade antimicrobiana, porém, para ser utilizado como alternativa para uso tópico, deve ter as características necessárias para ser incorporado em uma formulação que permita sua aplicação. Objetivo: As formas farmacêuticas semissól-idas são o grupo mais utilizado nas formulações dermatológicas; foram elaborados dois tipos de formulações, um tipo creme e outra creme-gel, a fim de verificar em qual delas o complexo [Cu(tnz)2(NO3)2] está convenientemente incorporado. Para ambas as formulações foram determinadas as propriedades organolépticas, pH, área de extensibilidade, viscosidade e tamanho de partícula do complexo. Resultados: Os obtidos mostram as vantagens da formulação tipo creme em relação ao gel-creme.

Evaluación in vitro de tabletas orales de complejos de cobre con antiinflamatorios no esteroideos / In vitro evaluation of oral tablets of copper-non steroidal anti inflammatory complexes

Introducción: los antiinflamatorios no esteroideos (AINES), son un grupo diverso y químicamente heterogéneo de fármacos analgésicos, antipiréticos y antiinflamatorios; sin embargo, su funcionamiento se ve afectado por su baja solubilidad acuosa y por la incidencia de efectos secundarios gastrointestinales. Como una alternativa a este problema, la formulación de tabletas orales con complejos de cobre con AINES muestra un adecuado comportamiento in vitro y podría tener efectos secundarios reducidos comparados con el fármaco antiinflamatorio no complejado. Objetivo: evaluar los procesos de desintegración y de disolución de tabletas orales de complejos de cobre con AINES. Métodos: luego de la síntesis y la caracterización instrumental de los complejos, se evaluó por microscopia óptica el efecto de la morfología, el tamaño de partícula y las características superficiales en el proceso de disolución; estos resultados fueron considerados para la formulación de los complejos y permitieron junto con la adecuada elección de un desintegrarte, un modificador de flujo, un lubricante y un aglutinante, la obtención de tabletas por compresión directa. Finalmente, en los comprimidos se evaluaron propiedades fisicomecánicas y los procesos de desintegración y disolución. Resultados: las tabletas de los complejos mostraron tiempos de desintegración entre 5 y 15 min y una liberación in vitro del 75 al 93 por ciento. Conclusiones: la disolución de los AINES se vio favorecida por la formación de complejos, el menor tamaño de partícula, la presencia de poros y grietas en la superficie de las partículas y la inclusión de excipientes para la formulación de tabletas orales(AU)

Introduction: non-steroidal anti-inflammatory drugs (NSAIDs) are a diverse and chemically heterogeneous group of analgesic, antipyretic and inflammatory drugs; however their performance is affected by low aqueous solubility and the incidence of side gastrointestinal effects. As an alternative to manage this problem, the copper-NSAIDS complex in a tablet formulation shows adequate in vitro behavior and might have minor side effects compared to those of the single non-complexed anti-inflammatory drug. Objective: to evaluate the tablet disintegration and dissolution behaviors of copper-NSAIDS complex. Methods: copper-NSAIDS complexes were synthesized and characterized. The effect of morphology, particle size and surface characteristics on the dissolution process was assessed through the optic microscopy. These results were further considered for the complex formulation and allowed the right selection of a disintegrator, a flow modifier, a lubricant and a binder together with production of tablets through direct compression. The mechanical and physical properties and the dissolution and disintegration behaviors of these compacts were also evaluated. Results: complex tablets showed disintegration times from 5 to 15 min and in vitro release of 75 percent to 93 percent. Conclusions: NSAIDs dissolution improved due to complexation with copper, smaller particle size, presence of pores and cracks on the particle surface and the inclusion of excipients in the formulation of oral tablets(AU)

Síntesis, caracterización fisicoquímica y del estado sólido de asparaginatos de cobre, magnesio, manganeso y zinc / Synthesis, physiochemical and solid state characterization of copper, magnesium, manganese and zinc asparaginates

Introducción: la deficiencia de minerales en la población está asociada a enfermedades metabólicas, hormonales e inmunológicas. Usualmente, los minerales son suplementados en el organismo en forma de sales inorgánicas, las cuales pueden causar molestias gástricas y baja absorción en dependencia del tipo de sal empleado. Estudios previos muestran una adecuada absorción y ausencia de efectos gástricos cuando los minerales están asociados a ligandos orgánicos como enzimas, proteínas y particularmente aminoácidos. Objetivo: determinar mediante un estudio de preformulación la viabilidad de utilizar asparaginatos de cobre, magnesio, manganeso y zinc en suplementos nutricionales. Métodos: se realizó la síntesis y la verificación de formación de los complejos por espectroscopia infrarroja por transformada de Fourier y difracción de rayos X de polvos. Se evaluó la solubilidad, la constante de disociación, la eficiencia de la disolución y las propiedades físicas del estado sólido (morfología, distribución y tamaño de partícula, índice de Haussner, porosidad y compresibilidad) de los complejos. Se determinó la compatibilidad de los complejos con excipientes. Resultados: en los espectros infrarrojos se observó la participación del grupo carboxilo de la asparagina en la formación del enlace de coordinación de los complejos. En los difractogramas de rayos X se mostró la ausencia de los materiales de partida y la cristalinidad en los complejos. La solubilidad, la constante de disociación y la eficiencia de la disolución de los complejos, establecieron su carácter anfótero. Conclusiones: los resultados en las propiedades físicas del estado sólido, la humedad y la compatibilidad con excipientes, establecen que las formulaciones de los aparaginatos de cobre, magnesio, manganeso y zinc tienen propiedades reológicas adecuadas para propósitos farmacéuticos.

Introduction: the mineral deficiency in the human population has been associated with metabolic, hormonal and immunological disorders. These minerals are generally supplemented with inorganic salts in the body, but they might cause gastric distress and low absorption problems depending on the type of salt used. Previous studies demonstrated adequate absorption and absence of gastric effects when minerals were associated with organic ligands such as enzymes, proteins and particularly amino acids. Objective: to determine the viability of copper, magnesium, manganese and zinc asparaginates as nutritional supplements in a preformulation study. Methods: the synthesis and verification of the formation of complexes were carried out by Fourier transformed infrared spectroscopy and X-ray diffraction of powders. The solubility, the dissociation constant, the dissolution efficiency and the physical solid state properties (morphology, particle distribution and size, Haussner´s index, porosity and compressibility) of these complexes were evaluated. The compatibility of the complex with excipients was determined. Results: the involvement of the asparagine carboxyl group in the formation of the coordination bond of the complex was observed in the infrared spectra. the absence of starting materials and the crystallinity in the complexes were evidenced in the X-ray diffraction of powders. The solubility, the dissociation constant and the dissolution efficiency of the complexes established their amphoteric character. Conclusions: the results achieved in the physical solid state properties, the level of moisture and the compatibility with the formulation excipients indicate that copper, magnesium, manganese and zinc asparaginates have suitable rheological properties for pharmaceutical purposes.

Evaluación de la dimensión fractal reactiva de los glicinatos de magnesio, manganeso y zinc / Evaluation of the reactive fractal dimension of magnesium, manganese and zinc glycinates

Introducción: complejos de glicina con los cationes magnesio, manganeso y zinc podrían ser parte de una formulación de un suplemento nutricional que proporcione una adecuada absorción de los metales en el organismo sin generar molestias gastrointestinales. Objetivo: realizar una aproximación a la solubilidad de los complejos de glicina con los cationes magnesio, manganeso y zinc. Métodos: se efectuaron estudios de disolución y análisis de imagen. Se realizó la síntesis y la verificación de formación de los complejos por espectroscopia infrarroja, calorimetría de barrido diferencial, análisis termogravimétrico y difracción de rayos X de polvos. Resultados: se obtuvieron por análisis de imagen los descriptores: circularidad, diámetro de Feret y dimensión fractal; esta última se relacionó con el proceso de disolución en agua, para obtener dos propiedades relacionadas: la dimensión fractal superficial y la dimensión fractal reactiva. Conclusiones: los resultados muestran que el proceso de disolución de los glicinatos, se realiza a través de los poros o grietas de la superficie de las partículas de estos y que son aptos para su empleo en formulaciones nutricionales como fuentes de magnesio, manganeso y zinc.

Introduction: Complexes of glycine and cations magnesium, manganese and zinc, could be included in the formulation of a nutritional supplement that provides adequate absorption of these metals into the body without gastrointestinal disturbances. Objective: to study the solubility of complexes of glycine and cations manganese, zinc and magnesium. Methods: dissolution and image analysis studies were performed. The synthesis and verification of the formation of complexes were carried out by infrared spectroscopy, differential scanning calorimetry, thermal gravimetric analysis, and X-ray diffraction of dust. Results: the image analysis showed some descriptors such as circularity, the Ferret diameter and the fractal dimension. The latter was related to the water dissolution process in order to obtain two associated properties, that is, the surface fractal dimension and the reactive fractal dimension, Conclusions: these results showed that the dissolution of glycinates occurs through the pores or cracks found in their particle surfaces and that these complexes are suitable for use in nutritional formulations as sources of magnesium, manganese and zinc.

Suplementos nutricionales orales a base de nuevos complejos de cobre, magnesio, manganeso y zinc

Suplementos nutricionales orales a base de nuevos complejos de cobre, magnesio, manganeso y zinc Los oligoelementos cobre, magnesio, manganeso y zinc intervienen en numerosos procesos metabólicos, enzimáticos, inmunológicos y tisulares, forman parte estructural de proteínas y pueden participar en la regulación de la expresión genética. La deficiencia de estos elementos esenciales dificulta el apropiado funcionamiento del organismo e induce el desarrollo de diversas enfermedades. Se debe garantizar la incorporación de oligoelementos a través de la dieta; sin embargo, la cantidad suministrada no siempre es suficiente y el uso de suplementos nutricionales convencionales presenta dos problemas; el primero se atribuye a la asociación de los metales a sales inorgánicas que generan una baja absorción e intolerancias a nivel gástrico y el segundo corresponde a las interacciones antagonistas entre diversos metales componentes de la formulación. Como una alternativa a los problemas mencionados, en este trabajo se propone la elaboración de tabletas para la administración oral de nuevos complejos de cobre, zinc, magnesio y manganeso ligados a los aminoácidos glicina y asparagina. En la síntesis de estos complejos, cada ligando se unió a duplas de cationes no antagonistas, se verificó la formación de los complejos por espectroscopía infrarroja, calorimetría de barrido diferencial, análisis termogravimétrico y difracción de rayos X de polvos, y se determinaron los tiempos de desintegración y de disolución in-vitro a las formas farmacéuticas finales.

Oral dietary supplements with copper, magnesium, manganese and zinc-based new complexes Oligoelements such as copper, magnesium, manganese and zinc are involved in several metabolic, enzymatic and immunological processes. They are also important for the integral tissue proteins and could be involved in gene expression regulation. The deficiency of these essential elements hampers the appropriate function of the body and may cause various diseases. Therefore, it is important to guarantee the incorporation of these trace elements in the diet, but the quantity provided is not always adequate for the optimum body performance. Currently, conventional nutritional supplements have two major problems. The first one is attributed to the association of inorganic salts with metals which might cause low absorption and gastric intolerance. The second problem is caused when several metals are present in a formulation which could lead to possible antagonistic interactions. For this reason, this study explores the development of cations (i.e., copper, zinc, magnesium and manganese) and amino acids (i.e., glycine and asparagine) new complexes formulated into compacts for oral administration. In each reaction, ligands were linked to non-antagonistic cation pairs. The complex formation was characterized by infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis and powder X-ray diffraction analyses. Compact disintegration and in-vitro dissolution tests for these complexes were also determined.

[Oral dietary supplements with copper, magnesium, manganese and zinc-based new complexes]. / Suplementos nutricionales orales a base de nuevos complejos de cobre, magnesio, manganeso y zinc.

Oligoelements such as copper, magnesium, manganese and zinc are involved in several metabolic, enzymatic and immunological processes. They are also important for the integral tissue proteins and could be involved in gene expression regulation. The deficiency of these essential elements hampers the appropriate function of the body and may cause various diseases. Therefore, it is important to guarantee the incorporation of these trace elements in the diet, but the quantity provided is not always adequate for the optimum body performance. Currently, conventional nutritional supplements have two major problems. The first one is attributed to the association of inorganic salts with metals which might cause low absorption and gastric intolerance. The second problem is caused when several metals are present in a formulation which could lead to possible antagonistic interactions. For this reason, this study explores the development of cations (i.e., copper, zinc, magnesium and manganese) and amino acids (i.e., glycine and asparagine) new complexes formulated into compacts for oral administration. In each reaction, ligands were linked to non-antagonistic cation pairs. The complex formation was characterized by infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis and powder X-ray diffraction analyses. Compact disintegration and in-vitro dissolution tests for these complexes were also determined.

Categorization of the main descriptors of different ampicillin crystal habits

With the purpose of enabling the analysis by digital methods of particles of multisource pharmaceutical raw materials, this study analyzed different crystal habits of ampicillin particles, by grouping the external shapes obtained from 3 different solvents (acetonitrile, ethanol, and methanol), thereby reducing the number of descriptors necessary to adequately represent each shape. For this purpose, a selection of morphological descriptors was used including: circularity, roughness, roundness, compactness, aspect ratio, effective diameter, solidity, convexity, fractal dimension, and 10 Complex Fourier descriptors. These measures cover highly diverse morphological properties and define the crystal habit of a particle. Principal Component Analysis (PCA) and the Cluster Analysis (CA) were the grouping techniques used, which demonstrated the possibility of using between 2 and 4 descriptors instead of the 18 proposed initially.

Com o objetivo de possibilitar a análise, por meio de métodos digitais, de partículas de matérias-primas farmacêuticas de múltiplas fontes, analisaram-se diferentes cristais de partículas de ampicilina através do agrupamento de formas externas obtidas de três diferentes solventes (acetonitrila, etanol e metanol), reduzindo, desse modo, o número de descritores necessários para representar adequadamente cada forma. Com esse propósito, utilizou-se seleção de descritores morfológicos, incluindo: circularidade, aspereza, arredondamento, compactação, relação de aspecto, diâmetro efetivo, solidez, convectividade, dimensão fractal e 10 descritores complexos de Fourier. Essas medidas cobrem diversas propriedades morfológicas e definem a cristalinidade de uma partícula. As análises do componente principal (PCA) e por grupamento (CA) foram as técnicas de agrupamento utilizadas, que demonstraram a possibilidade de utilizar entre 2 e 4 descritores ao invés dos 18, inicialmente propostos.

Low temperature crystal structure of natural diosgenone.

The molecular structure of diosgenone, a natural steroidal sapogenin, closely related to diosgenin and isolated from Solanum nudum, was solved by single crystal X-ray diffractometry at 120 K and refined by full-matrix least-squares to an agreement factor, R1 = 0.054. It crystallizes in the monoclinic space group P2(1), with a = 15.1870(4) A, b = 7.2710(2) A, c = 21.2840(6) A, beta = 99.251(1) degrees, and four molecules in the unit cell (Z = 4). The results constitute the first structural report on a steroidal sapogenin from the diosgenin group.