Polymorphism of Anti-HIV Drug Efavirenz: Investigations on Thermodynamic and Dissolution Properties

Polymorphs, cocrystals, solvates, and hydrates have been reported for efavirenz (EFV), which is part of high activity antiretroviral therapy (HAART), and it is considered to be the best choice in the treatment of adults and children. However, studies about thermodynamic stability and improvement of dissolution properties have been rarely reported for the anhydrous polymorphic forms. Therefore, the aim of this work was to characterize the solid state of anhydrous polymorph I and polymorph II (herein obtained), to study the thermodynamic stability and strategies to improve the dissolution properties. in addition, techniques such as, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), hot stage microscopy (HSM), scanning electron microscopy (SEM), Fourier transform infrared (FT-IR), raman spectroscopy (RS), theoretical calculations, and solid-state nuclear magnetic resonance (ss-NMR) were used to complete this work. Thermodynamic studies showed that polymorphs I and II are enantiotropically related with the isoenergetic point between 35 and 40 degrees C. the EFV polymorph II showed itself to be more stable and 10-fold more soluble than polymorph I, due to modifications of morphology. Therefore, polymorph II could be an excellent candidate with significant advantages for pharmaceutical formulations.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)FAPESCCLAFFundacion SauberanPDTIS/FIOCRUZUniv Fed Santa Catarina, Lab Controle Qualidade, BR-88040900 Florianopolis, SC, BrazilUniv Costa Rica, Escuela Quim, San Jose 2060, Costa RicaUniv Fed Santa Catarina, Dept Fis, Lab Difracao RaioX, BR-88040900 Florianopolis, SC, BrazilFiocruz MS, Inst Tecnol Farmacos Farmanguinhos, Lab Sistemas Farmaceut Avancados, BR-22775610 Rio de Janeiro, BrazilUniv Nacl Cordoba, FaMAF, RA-5000 Cordoba, ArgentinaIFEG CONICET, RA-5000 Cordoba, ArgentinaUniversidade Federal de São Paulo, Posgrad Engn & Ciencias Mat, BR-12231280 São Paulo, BrazilUniversidade Federal de São Paulo, Posgrad Engn & Ciencias Mat, BR-12231280 São Paulo, BrazilWeb of Scienc