Impact of the crystallization conditions on the polymorphism and crystalline size domain of Efavirenz

Full text: Efavirenz (EFV) is a compound used in High Activity Antiretroviral Therapy (HAART). A very critical problem in using drugs with low solubility is to assure their bioavailability. Previous studies have shown that dissolution rate, as well as a bioequivalence of EFV depend on microstructure of its crystalline phase. However, the pharmaceutical industry does not include the control of this solid state property in quality control steps of EFV. In order to study the variability of the microstructure and other solid state properties, the samples of EFV were crystallized from solution at different crystal growth conditions: temperature, agitation and type of solvent. The produced samples were characterized by the X-ray powder diffraction method using synchrotron radiation (XPD beamline). X-ray diffraction patterns obtained using conventional X-ray sources allowed for identification of polymorph present in the samples. However, a reliable determination of the average crystallite sizes for each sample required the use of synchrotron radiation. A combination of a highly crystalline powder sample of EFV and the standard reference material, Al₂O₃ (NIST, SRM 1976), was used to determine the instrumental aberrations, mainly, at low 2-Q diffraction angles, as there is no available standard reference material that covers low 2-Q angle range typical for drugs diffraction. X-ray powder diffraction data were analyzed by Rietveld refinement method using TOPAS Academic software. It was established that crystal nucleation temperatures determine the EFV´s polymorphism incidence while crystalline domain sizes, in turn, depend on polymorphism. Important correlations between type of solvent and agitation conditions, on the one hand, and crystalline size domain, on the other hand, are reported. (author)