RESUMEN
Telmisartan (TEL) was entrapped into ß-cyclodextrin aiming the improvement of its biopharmaceutical properties of low solubility. A solid state grinding process was used to prepare the molecular inclusion complex (MIC) for up to 30min. The inclusion ratio of drug and ß-cyclodextrin was established as 1:2 and 1:3 (mol/mol) by phase solubility study and Job Plot. DSC, XRPD and FTIR confirmed the molecular interactions between TEL and ß-cyclodextrin. Computer molecular modeling supports the presence of hydrogen bonds between guest and host and demonstrated the most probable complexes configuration. MIC_1:2_30 and MIC_1:3_30 enhanced the dissolution rate of the drug achieving a delivery rate comparable with the reference medicine available in the market (81% and 87% in 5min, for MIC_1:3_30 and Micardis(®), respectively). These formulations showed rapid and effective antihypertensive effect against angiotensin II in rats up to 180min, with statistically significant results against placebo and control in the first 30min after administration.
Asunto(s)
Antihipertensivos/química , Bencimidazoles/química , Benzoatos/química , Fenómenos Mecánicos , beta-Ciclodextrinas/química , Animales , Antihipertensivos/farmacología , Conformación de Carbohidratos , Química Farmacéutica , Femenino , Modelos Moleculares , Ratas , Ratas Wistar , Solubilidad , Telmisartán , beta-Ciclodextrinas/farmacologíaRESUMEN
Here we report the structural characterization, physicochemical study and molecular modeling of the inclusion complex of trimethoprim in randomly methylated beta-cyclodextrin. The phase-solubility diagram obtained at pH 7.0 exhibited a linear behavior for the RAMEB concentrations studied suggesting a 1:1 stoichiometry and absence of aggregation in solution. From stoichiometric determination by the continuous variation method we confirmed a 1:1 stoichiometry. To make a detailed characterization of the inclusion mode, spectroscopic measurements by infrared and 1D and 2D (1)H NMR spectroscopy provided evidence that the inclusion mode is characterized by inclusion of the trimethoxyphenyl ring in the cavity; interactions with methyl groups located in the border of the cavity were also detected. The structure proposed was also confirmed by semiempirical molecular modeling.
Asunto(s)
Portadores de Fármacos/química , Trimetoprim/química , beta-Ciclodextrinas/química , Química Farmacéutica , Estabilidad de Medicamentos , Espectroscopía de Resonancia Magnética , Metilación , Modelos Químicos , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Termodinámica , Temperatura de TransiciónRESUMEN
An inclusion complex between the dihydrofolate reductase inhibitor pyrimethamine (PYR) and alpha-cyclodextrin (alpha-CD) was prepared and characterized. From the phase-solubility diagram, a linear increase of PYR solubility was verified as a function of alpha-CD concentration, suggesting the formation of a soluble complex. A 1:1 host-guest stoichiometry can be proposed according to the Job's plot, obtained from the difference of PYR fluorescence intensity in the presence and absence of alpha-CD. Differential scanning calorimetry (DSC) measurements provided additional evidences of complexation such as the absence of the endothermic peak assigned to the melting of the drug. The inclusion mode characterized by two-dimensional (1)H NMR spectroscopy (ROESY) involves penetration of the p-chlorophenyl ring into the alpha-CD cavity, in agreement to the orientation optimized by molecular modeling methods.
Asunto(s)
Modelos Moleculares , Pirimetamina/química , alfa-Ciclodextrinas/química , Espectroscopía de Resonancia Magnética , Solubilidad , Termodinámica , Difracción de Rayos XRESUMEN
In this work we prepared and characterized an inclusion complex of the dihydropteroate synthase inhibitor sulfadiazine (SDZ) in 2-hydroxypropyl-beta-cyclodextrin (HPBCD). From the phase-solubility diagram we observed an increase in the water solubility of the drug, calculating a binding constant of 1879M(-1). The inclusion mode involves a NH(2)-in orientation of the drug in the HPBCD cavity, according to the 2D NMR (ROESY) data and confirmed by molecular modeling using the semiempirical PM6 and RM1 methods.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Sulfadiazina/química , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina , Fenómenos Químicos , Química Física , Dihidropteroato Sintasa/antagonistas & inhibidores , Portadores de Fármacos/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Espectroscopía de Resonancia Magnética/métodos , Modelos Moleculares , Estructura Molecular , Transición de Fase , Solubilidad , Relación Estructura-Actividad , Temperatura , Agua/química , Difracción de Rayos XRESUMEN
The inclusion complexation of pyrimethamine in 2-hydroxypropyl-beta-cyclodextrin has been investigated by 2D (1)H NMR, FTIR and UV/visible spectroscopy and also by molecular modelling methods (AM1, PM3, MM3). From the phase-solubility diagram a linear increase was observed in pyrimethamine aqueous solubility in the presence of 2-hydroxypropyl-beta-cyclodextrin, evidencing the formation of a soluble inclusion complex. According to the continuous variation method (Job's plot) applied to fluorescence measurements, a 1:1 stoichiometry has been proposed for the complex. Concerning the structure of the complex, a Cl-in orientation of pyrimethamine in the 2-hydroxypropyl-beta-cyclodextrin cavity has been proposed from the theoretical calculations, being confirmed by two-dimensional (1)H NMR spectroscopy (ROESY). The thermal behaviour has also been studied, providing complementary evidences of complex formation.