Estudos de pré-formulação em fosamprenavir

Abstract

Preformulation studies comprise a relevant stage of the drug research and development process. They include solid-state physical-chemical characterization and evaluation of drug stability. The present study evaluated the polymorphic stability of the drug fosamprenavir calcium and its chemical stability through forced degradation tests and drug-excipient compatibility studies. Fosamprenavir calcium was obtained from Telzir® and characterized by nuclear magnetic resonance (NMR), spectroscopy Fourier Transform infrared (FTIR), mass spectrometry (MS), powder X-ray diffraction (PXRD), single X-ray diffraction (SXRD), thermogravimetry (TG), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). A stability indicating high performance liquid chromatography (HPLC) method was development and used to verify the purity of fosamprenavir calcium obtained, to evaluate its intrinsic stability through forced degradation studies and to be employed in the compatibility tests. The obtained drug showed a chromatographic purity of 99.95%, compatible to be used as working standard. On forced degradation studies, fosamprenavir was stable under thermal, humidity, photolysis and neutral hydrolysis. Significant degradation was observed when the drug was subject to acid and base hydrolysis and oxidative conditions. Two degradation products were characterized by tandem mass spectrometry and their reactional mechanisms were proposed. On the drug-excipient compatibility studies the samples were analyzed immediately after preparation using FTIR and HPLC. Afterwards they were incubated in a stability chamber at 40ºC ± 2ºC and 75% ± 5% of relative humidity and analyzed again after 3 and 6 months of incubation. Fosamprenavir calcium has shown to be chemically compatible with the excipients povidone K-30, crospovidone, croscarmellose sodium, opadry, starch, magnesium stearate and colloidal anhydrous silica. For the evaluation of the polymorphic stability of the drug, the results of incubated samples were compared with the initial results by FTIR and PXRD. The results demonstrated that the crystalline form I of fosamprenavir calcium is stable under the conditions evaluated.