Estudo de compatibilidade e avaliação da dissolução in vitro de formulações comerciais contendo fluconazol segundo os critérios da bioisenção

Abstract

The biowaiver of bioequivalence studies on class I drugs of the biopharmaceutics classification system (BCS) is aimed mainly at reducing the costs and the exposure of health volunteers to a new pharmaceutical formulation. Fluconazole is an important antifungal agent but in the literature it is not clear whether it belongs to BCS class I or III. The aim of this study was to qualitatively determine the composition of commercially available fluconazole formulations in the form of capsules, to carry out compatibility studies drug/excipient, to develop and validate methodology by high performance liquid chromatography (HPLC) to quantify the drug and compare the in vitro dissolution profiles of reference, generic and similar formulations, verifing the compliance with the criteria established for biowaiver. One formulation did not contain sodium lauryl sulfate and contained mannitol, in contrast to the reference formulation, which could hinder the acceptance of the biowaiver. The interaction of fluconazole with microcrystalline cellulose and calcium hydrogen phosphate dihydrate was observed by Differential scanning calorimetry (DSC); however, no indication of incompatibility was found in the DSC analysis of the commercial pharmaceutical formulations. These interactions were also studied by Fourier transform infrared spectroscopy, where small changes in the bands were observed, and by X-ray Powder diffraction and scanning electron microscopy, that did not evidenced any modification in the solid state characteristics. The method developed and validated by HPLC to quantify the fluconazole showed linearity, specificity, precision, accuracy, satisfactory robustness and limits of quantification and detection, thus ensuring the reliability of the results. According to RDC 37/2011 to be a biowaiver candidate the formulation should be considered as rapid dissolution, i.e., not less than 85% of the total amount of drug contained in the formulation dissolves within 30 minutes. All tested formulations in simulated gastric fluid (pH1.2) met the specification. With acetate buffer (pH 4.5), all generic and one similar formulations complied the recommendations, and with simulated intestinal fluid (pH 6.8) only two generic and one similar showed a percentage of dissolution above 85%. Thus, it was shown that not all available commercial formulations met with the creteria established by RDC 37/2011. However, it should not be a concern for the patient, since they were subjected to in vivo analysis before approval by ANVISA.