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Solubilization and solid-state characterization of a poorly soluble 5-Alpha Reductase Inhibitor

Drug Dev Ind Pharm. 2004 Jul;30(6):573-80.
Zhu HJ, Sacchetti M.
Strategic Technologies, GlaxoSmithKline Inc., Research Triangle Park, North Carolina, USA.

GI197111X is a 5-alpha reductase inhibitor for the treatment of androgenetic alopecia. Equilibrium solubilities of GI197111X were determined in multiple solvents or cosolvents. A polymorph screen was conducted using suspension equilibration and solution recrystallization methods. Single crystals were grown from pyridine/water and crystal structure was determined using a Bruker SMART diffractometer. Crystal structure data were imported into Cerius2 to provide visualization of the crystal structure and calculation of the simulated X-ray powder diffraction (XRPD) pattern. The solubility of GI19711IX was low at 25 degrees C in all vehicles suitable for animal and human dosing. The solubility of 6.4 mg/mL in Capmul MCM made it the only choice for a soft gel dosage form for phase I/II. Solution recrystallization and suspension equilibration of GI197111X have produced only one crystal form. Crystal structure data: orthorhombic P2(1) 2(1) 2(1); a= 10.8960(6) A, b=11.5683(6) A, c=20.9019(11) A; unit cell volume 2634.65(24) A3; Z=4; calculated density= 1.248 g/cc. The molecule has seven chiral centers, and single-crystal analysis eliminated all possible stereo-isomers except the expected conformation or its enantiomer. Hydrogen bonds occur from both carbonyl oxygens to an H-N group. Simulated vacuum-based crystal morphology (habit) calculated using the Bravais-Friedel-Donnay-Harker, Growth Morphology, and Hartman-Perdok modules in Cerius2 was a close match to the morphology observed by light microscopy.


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