Thermal analysis and determination of the kinetic parameters of preparations pharmaceutical and new specialties zidovudine (AZT)

Author(s)

Adriano Antunes de Souza Araújo

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
• Defense date: 2003-05-16

Examining board members

Jivaldo do Rosario Matos; Roy Edward Bruns; Fernando Luis Fertonani; Massao Ionashiro; Davi Pereira de Santana

• Advisor: Jivaldo do Rosario Matos; Silvia Storpirtis

Abstract

For over twenty years the dissemination of the human immunodeficiency virus (HIV) appeared in the world. Since then, considerable advances in the diagnosis, clinic and therapy have been observed currently three classes of drugs 14 agents are in use for HIV infection. Therefore, the long-term effectiveness of potent three-drug antiretroviral regimens for the treatment of HIV infected patients and/or patients with adquired immunodeficiency syndrome (SIDA) is limited by problems related to compliance and tolerability. The aim of this work to apply the pharmaceutical technology to the production and control of anti-HIV/SIDA drugs and medicines, especially for zidovudine (AZT). The use of different physico-chemical and analytical techniques rnade it possible to develop some related studies for the stability evaluation and thermal decomposition of AZT, excipients and physical mixtures used for obtaining solid dosage forms; characterization of the solid and volatiles products of the thermal degradation process of AZT; determination of the purity, melting point and enthalpy variation of AZT obtained from different laboratories; synthesis and characterization of AZT inclusion compounds with cyclodextrins and with lanthanides salts characteristically luminescent; evaluation of the accelerated stability and the long-time of AZT capsules available in the Brazilian Market; determination of the degradation kinetics parameters of the different AZT samples. The factorial design method was used in the statistical evaluation of the kinetic data obtained from non-isothermal thermogravimetry (TG). The pre-formulation studies by thermal analysis indicated that there were no interaction between the AZT and the majority of the tested excipients. Some changes in the thermoanalytical profiles were observed in relation to PEG 4000, 6000 and 20000, PVP, sorbitol and ethylene polyoxide (polyox 30®) excipients. In the thermal decomposition process of AZT was observed the formation of thymine. The use of simultaneous and coupled system TG/DTA-GC/MS made it possible to identify of furan and 2-furanmethanol as volatiles products. The differential scanning calorimetry experiments permitted the determination of the melting point (118,0 to 122,9°C), ΔHmelting (medium value 30 kJ.min-1) and purity percentage (97,5 a 99,8%) for six commercial samples of the drug. The inclusion complex of AZT/β-cyclodextrin was obtained by the dissolution of the species in water and the mixture was dried by lyophilization or under vacuum at room temperature. The interaction between the species do not occur in the simple physical mixture. In this work, thenoyltrifluoroacetonate complexes with trivalent europium and samarium were prepared using AZT as a ligand. The complex presented high luminescence. According to the results of IR spectroscopy of the complexes [RE(TTA)3·(AZT)2], it was suggested that the metal ion be coordinated through the nitrogen of the azide group. The powder X-ray diffractometry (DRX) indicated that the complexes [Eu(TTA)3·(AZT)2] are not crystalline while free AZT, hydrate precursor salt [RE(TTA)3·2H2O] and physical mixture are. The variability study of the influence of different experimental conditions from TG, using Factorial Design, showed that none of the effects are significative. The kinetic energy values for the commercial AZT samples varied between 120 to 142 kJ.mol-1, by non-isothermal conditions, and 100 to 112 kJ.mol-1, by dynamic method. The results obtained in the kinetic studies are reproducible. These parameters are important for the evaluation of pharmaceutical equivalence together with bioequivalence studies. (AU)