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.
- Research Organization:
- SLAC National Accelerator Lab., Menlo Park, CA (United States)
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- AC02-76SF00515
- OSTI ID:
- 953540
- Report Number(s):
- SLAC-REPRINT-2009-343; TRN: US1000845
- Journal Information:
- Mol. Pharmaceutics 5:956,2008, Vol. 5, Issue 6; ISSN 1543-8384
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
AQUEOUS SOLUTIONS
AUGMENTATION
BEHAVIOR
CALORIMETRY
DISSOLUTION
DISTRIBUTION
ETHANOL
INTERFACES
LEVELS
LIQUID CRYSTALS
LIQUIDS
MOLECULES
MORPHOLOGY
OPTICAL MICROSCOPY
SCATTERING
SIZE
SOLUBILITY
SOLUTIONS
SUPERSATURATION
SURFACE TENSION
SUSPENSIONS
SYNCHROTRONS
TRANSFORMATIONS
WATER
X-RAY DIFFRACTION
Other
OTHER