Organic synthesis in a modular robotic system driven by a chemical programming language.

The synthesis of complex organic compounds is largely a manual process that is often incompletely documented. To address these shortcomings, we developed an abstraction that maps commonly reported methodological instructions into discrete steps amenable to automation. These unit operations were implemented in a modular robotic platform by using a chemical programming language that formalizes and controls the assembly of the molecules. We validated the concept by directing the automated system to synthesize three pharmaceutical compounds, diphenhydramine hydrochloride, rufinamide, and sildenafil, without any human intervention. Yields and purities of products and intermediates were comparable to or better than those achieved manually. The syntheses are captured as digital code that can be published, versioned, and transferred flexibly between platforms with no modification, thereby greatly enhancing reproducibility and reliable access to complex molecules.

Palladium-Catalyzed 2,2,2-Trifluoroethoxylation of Aromatic and Heteroaromatic Chlorides Utilizing Borate Salt and the Synthesis of a Trifluoro Analogue of Sildenafil.

A simple and convenient method was developed for the introduction of a 2,2,2-trifluoroethoxy group to various aromatic and heteroaromatic systems. The novel process utilizes aromatic chlorides as substrates, and tetrakis(2,2,2-trifluoroethoxy) borate salt as an inexpensive and readily available fluoroalkoxy source in a palladium-catalyzed cross-coupling reaction. The power of the developed methodology was demonstrated in the synthesis of a fluorous derivative of Sildenafil.

ATR-FTIR characterization of generic brand-named and counterfeit sildenafil- and tadalafil-based tablets found on the Brazilian market.

Viagra and Cialis are among the most counterfeited medicines in many parts of the world, including Brazil. Despite the many studies that have been made regarding discrimination between genuine and counterfeit samples, most published works do not contemplate generic and similar versions of these medicines and also do not explore excipients/adjuvants contributions when characterizing genuine and suspected samples. In this study, we present our findings in exploring ATR-FTIR spectral profiles for characterizing both genuine and questioned samples of several generic and brand-name sildenafil- and tadalafil-based tablets available on the Brazilian market, including Viagra and Cialis. Multi-component spectral matching (deconvolution), objective visual comparison and correlation tests were used during analysis. Besides from allowing simple and quick identification of counterfeits, results obtained evidenced the strong spectral similarities between generic and brand-named tablets employing the same active ingredient and the indistinguishability between samples produced by the same manufacturer, generic or not. For all sildenafil-based and some tadalafil-based tablets tested, differentiation between samples from different manufacturers, attributed to slight variations in excipients/adjuvants proportions, was achieved, thus allowing the possibility of tracing an unknown/unidentified tablet back to a specific manufacturer.

New approaches to the synthesis of sildenafil analogues and their enzyme inhibitory activity.

In the search for new biologically active chemotypes, several sildenafil analogs were prepared and characterized. The presence of the pyrazolo[4,3-e][1,2,4]triazine core is thought to be of interest for the enzyme inhibitory activity of these compounds. The designed derivatives incorporating the sildenafil scaffold were assayed as carbonic anhydrase inhibitors, and for their cytotoxic activity against MCF-7 and K562 cell lines. The X-ray analysis of one of these model compounds was performed and its crystal structure is described/compared to that of sildenafil.

Estudio comparativo de estabilidad de tres formulaciones magistrales de Sildenafil bajo la forma de solución, obtenidas a partir de diferentes productos comerciales / Comparative study stability of the three master formulation of Sildenafil solution obtained from differents trademarks

El Sildenafil es un fármaco de comprobada actividad terapéutica en la disfunción eréctil; se encuentra disponible bajo la forma farmacéutica de tabletas de administración oral. En la actualidad se está formulando magistralmente en forma de so lución oral a una concentración de 1mg/ml, para la hipertensión pulmonar (HP), por lo que se ha planteado realizar un estudio de la estabilidad en tres condiciones: ambientales (25±-2 ºC), de refrigeración (5±3 ºC) y exageradas de almacenamiento (40 ºC ± 2 ºC). Los parámetros evaluados fueron apariencia, limpidez, densidad, pH y contenido de sildenafil. El método analítico empleado fue cromatografía líquida de alta resolución (HPLC) de fase reversa. La apariencia, los valores de pH y densidad de las soluciones obtenidas se mostraron sin cambios significativos, en las diferentes muestras y condiciones de estudio. En cuanto a los resultados del contenido inicial de sildenafil se obtuvo aproximadamente el 75% en peso al formular la solución, partiendo del comprimido. Cabe señalar que se observó discrepancia en los valores de concentración del sildenafil obtenidos en los diferentes tiempos y condiciones; resultados éstos de esperarse por tratarse de una formulación magistral que parte de comprimidos de diferentes casas comerciales, por lo que este estudio permitió sugerir que la formulación magistral se reformule a la forma farmacéutica de suspensión, para garantizar el contenido de todo el principio activo en la misma.

Sildenafil is a drug with proven therapeutic activity in erectile dysfunction is available under the pharmaceutical form of tablets for oral administration. It is currently being de veloped skillfully in an oral solution at a concentration of 1mg/ml, for pulmonary hypertension (pH), as has been planned to perform a study of stability in three conditions: environmental (25 ± 2 ºC), refrigeration (5 ± 3 ºC) and exaggerated storage (40 °C ± 2 ºC). The parameters evaluated were appearance, clarity, density, pH and content of sildenafil. The analytical method used was high performance liquid chromatography (HPLC) reverse phase. The appearance, pH and density of the solutions were no significant changes in the different samples and study conditions. As for the results of the initial content of sildenafil was obtained about 75% by weight in for mulating the solution, based on the tablet. It should be noted that there was discrepancy in the values of concentration of sildenafil obtained at different times and conditions, results they expected because it is a masterly formulation of tablets of different business houses, so this study suggest that the wording allowed masterful be reformulated to the pharmaceutical form of suspension, to ensure the contents of the entire active.