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.
Rodríguez-Spong
Barbara
B
Department of Pharmaceutical Sciences, University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109-1065, USA.
Acciacca
Alison
A
Fleisher
David
D
Rodríguez-Hornedo
Naír
N
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