Cloridrato de naltrexona: estabilidade de polimorfos hidratados e avaliação da degradação em condições ácidas e básicas

Abstract

In this work, it was studied the crystalline stability, and the chemical degradation profile, of the drug CNTX, purchased by compounding pharmacy. Initially, CNTX was characterized by XRD, NMR of 1H and 13C, FTIR, HPLC-MS and TG-DTA techniques. By XRD analysis and refinement by the Rietveld method -using comparison with data reported in the Cambridge Structural Database System (CSDS) – it was not possible the identification of IFA crystalline structure; which was recrystallized in aqueous solution. The CNTX tetrahydrate structure formation, in an aqueous medium, was confirmed by the XRD and TG-DTA data. The crystalline stability of CNTX tetrahydrate was evaluated by XRD analysis through measurements carried out in a nitrogen atmosphere. The experiment showed the conversion of the tetrahydrate structure to the anhydrous CNTX structure after 15 minutes. The characterization of the crystalline phase by XRD leads to the identification of the CNTX dihydrate in the pharmaceutical formulation analyses. Besides, experiments on the crystalline stability of naltrexone hydrochloride present in the formulation over one year, showed that the dihydrate structure remained unchanged. Aiming to perform studies with naltrexone in the form of a free base, the formulation was subjected to acid-base treatment followed by ethyl acetate extraction. After solvent removal, the crystals obtained were analyzed by single-crystal XDR method and identified as two novel crystalline forms of the naltrexone solvates: the ethyl acetate, and the diethyl ether solvate. Regarding the chemical degradation study, naltrexone hydrochloride was subjected to degradation conditions in hydrolytic medium (0.1 M HCl and 0.1M NaOH), followed with LC-MS analysis for the final aqueous solution. In basic medium solution, it was possible to observe the drug degradation and impurity formation in an oxidized form, reported per European Pharmacopoeia as impurity G or F.