       Document 0215
 DOCN  M9640215
 TI    Preformulation studies of a novel HIV protease inhibitor, AG1343.
 DT    9604
 AU    Longer M; Shetty B; Zamansky I; Tyle P; Department of Pharmaceutical
       Development, Agouron Pharmaceuticals; Inc., San Diego, CA 92121, USA.
 SO    J Pharm Sci. 1995 Sep;84(9):1090-3. Unique Identifier : AIDSLINE
       MED/96079220
 AB    AG1343 is a novel human immunodeficiency virus (HIV) protease inhibitor
       designed using protein structure-based techniques and intended for
       chronic oral administration in the treatment of AIDS-related conditions.
       The compound is the mesylate salt of a basic amine with a molecular
       weight of 663.90, pKa of 6.0, and partition coefficient (log P) of 4.1.
       Examination of the physicochemical properties of a bench-scale lot of
       the bulk drug was undertaken in order to establish a preformulation
       database and to begin development of an oral formulation suitable for
       phase I clinical trials. A stability-indicating gradient HPLC method was
       developed, and initial stability studies indicated that the compound is
       relatively stable under accelerated conditions. Water solubility and
       intrinsic dissolution rate studies, however, revealed the potential for
       dissolution rate-limited absorption. Alternative salts were prepared and
       evaluated for water solubility relative to the mesylate. A pH-solubility
       profile for AG1343 was generated and its solubility in various
       pharmaceutical solvents was determined. Formulation into several
       prototypical oral dosage forms for in-vitro evaluation in animal models
       prior to phase I clinical trials resulted in a several-fold difference
       in bioavailability between these formulations.
 DE    Animal  Antiviral Agents/ADMINISTRATION & DOSAGE/*CHEMISTRY/
       PHARMACOKINETICS  Biological Availability  Calorimetry, Differential
       Scanning  Chromatography, High Pressure Liquid  Dogs  Drug Stability
       Hydrogen-Ion Concentration  HIV Protease Inhibitors/ADMINISTRATION &
       DOSAGE/*CHEMISTRY/  PHARMACOKINETICS  Microscopy, Polarization  Rats
       Rats, Sprague-Dawley  Solubility  X-Ray Diffraction  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

