Solubilization and solid-state characterization of a poorly soluble 5-alpha reductase inhibitor.

Abstract

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.

• Authors: Haijian Jim Zhu, Mark Sacchetti
• Journal: Drug development and industrial pharmacy (Drug Dev Ind Pharm) Vol. 30 Issue 6 Pg. 573-80 (Jul 2004) ISSN: 0363-9045 [Print] England
• PMID: 15285330 (Publication Type: Journal Article)

Chemical References

• GI197111X
• Indoles
• Quinolines
• Suspensions
• Cholestenone 5 alpha-Reductase

Topics

• Calorimetry, Differential Scanning
• Cholestenone 5 alpha-Reductase (antagonists & inhibitors)
• Chromatography, High Pressure Liquid
• Crystallization
• Crystallography, X-Ray
• Drug Stability
• Indoles (chemistry)
• Models, Molecular
• Quinolines (chemistry)
• Solubility
• Surface Properties
• Suspensions
• X-Ray Diffraction