ESTUDO FISICO-QUÍMICO DO COMPLEXO DE INCLUSÃO DO FÁRMACO TRIMETOPRIM COM A β CICLODEXTRINA ALEATORIAMENTE METILADA / STUDY OF PHYSICAL-CHEMICAL INCLUSION COMPLEX DRUG TRIMETHOPRIM WITH RANDOM METHYL Β CYCLODEXTRIN

AUTOR(ES)
DATA DE PUBLICAÇÃO

2010

RESUMO

Cyclodextrins are well-known as good solubilizers for many drug molecules, since they are capable of increasing the solubility of the drugs by the formation of inclusion complexes, which in turn can be used in pharmaceutical formulations. In this work we aimed to prepare and characterize inclusion complexes of the randomly methylated β-cyclodextrin (RAMEB) and the antibiotic drug trimethoprim (TMP). The inclusion complex has been prepared by the suspension method and a kinetic study of the inclusion process allowed us to determine that a contact time of 24 hours is necessary for the equilibrium establishment. The inclusion complex in the solid state has been characterized by TG, DSC, FTIR, XRD, uni- and bidimensional 1H NMR spectroscopy (ROESY). Three different media were chosen for the study of the solution behavior: water, acid (pH 4.0) and basic (pH 9.0). The occurrence of inclusion has been evidenced primarily by the increase of the solubility of TMP in the presence of RAMEB according to the phase-solubility diagrams. The phase-solubility diagram obtained in acid medium, water and basic medium exhibited respectively the characteristic AL, BS, AN profiles. The AL profile is related to linear increasing in the solubility with increasing CD concentration, in contrast to the other profiles. The phase-solubility diagrams also provide a means of determining the values of association constants, in the case of linear behavior. Here a value of 754,9 L.mol-1 has been found for the formation in acid medium, indicating that formation of the complex is favored in this medium. A 1:1 stoichiometry was found for the inclusion complex both from the phase-solubility and from the Job Plot, as known as continuous variation method. Additional evidences of complexation were provided by TG analysis which showed an increasing of TMP stability when complexed to RAMEB. From NMR spectroscopy it was possible to evaluate the orientation adopted by drug molecules inside the RAMEB cavity. From this result, it became clear that TMP is included in the cavity through the trimethoxyphenyl ring, according to cross-peaks that indicate proximity in space between protons from this ring and protons from the RAMEB cavity.

ASSUNTO(S)

quimica solubilidade complexo de inclusão inclusion complex solubility trimetoprim trimethoprim

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