PH-induced nanosegregation of ritonavir to lyotropic liquid crystal of higher solubility than crystalline polymorphs.
Birefringent spherical vesicles of ritonavir (RTV) are formed by increasing the pH of aqueous solutions from 1 to 3 or to 7 and by addition of water to ethanol solutions at room temperature. Increasing the pH creates supersaturation levels of 30-400. Upon this change in pH, the solutions become translucent, implying that some kind of RTV assembly was formed. Small spherical vesicles of narrow size distribution are detectable only after a few hours by optical microscopy. The vesicles show similar X-ray diffraction patterns and differential scanning calorimetry (DSC) behavior to amorphous RTV prepared by melt-quenching crystalline RTV. Examination by polarized optical microscopy suggests that these are lyotropic liquid crystalline (LLC) assemblies. Small-angle X-ray scattering and synchrotron X-ray diffraction further support the presence of orientational order that is associated with a nematic structure. RTV self-organizes into various phases as a result of the supersaturation created in aqueous solutions. The LLC vesicles do not fuse but slowly transform to the polymorphs of RTV (in days), Form I and finally Form II. Amorphous RTV in aqueous suspension also undergoes a transformation to a mesophase of similar morphology. Transformation pathways are consistent with measured dissolution rates and solubilities: amorphous > LLC >> Form I > Form II. The dissolution and solubility of LLC is slightly lower than that of the amorphous phase and about 20 times higher than that of Form II. RTV also self-assembles at the air/water interface as indicated by the decrease in surface tension of aqueous solutions. This behavior is similar to that of amphiphilic molecules that induce LLC formation.
Department of Pharmaceutical Sciences, University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109-1065, USA.
Barbara
B
Rodríguez-Spong
Alison
A
Acciacca
David
D
Fleisher
Naír
N
Rodríguez-Hornedo
D011232:Chemical Precipitation; D003460:Crystallization; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D050866:Liquid Crystals / Q000737:chemistry*; D015394:Molecular Structure; D044367:Phase Transition; D019438:Ritonavir / Q000737:chemistry*; D012995:Solubility; D012996:Solutions; D013500:Surface Tension; D044366:Transition Temperature; D014867:Water / Q000737:chemistry
D017320:HIV Protease Inhibitors; D012996:Solutions; D014867:Water; D019438:Ritonavir