Spectroscopic identification of an amorphous-to-crystalline drug transition in a solid dispersion SCH 48461 capsule formulation.
Changes in the dissolution of a solid dispersion capsule formulation composed of amorphous SCH 48461 in a polyethylene glycol 8000 matrix were investigated. SCH 48461 [(3R,4S)-1,4-bis(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone] is a potent cholesterol absorption inhibitor with low water solubility and low melting point. Several capsule lots placed under controlled storage conditions exhibited a slowing of dissolution as a function of time with large inter-lot and intra-lot dissolution variations. Capsule contents were analyzed by attenuated total reflectance infrared (ATR-IR) microspectroscopy and solid-state cross-polarization, magic angle spinning (CPMAS) 13C-nuclear magnetic resonance (NMR) spectrometry. ATR-IR microspectroscopic analysis showed large IR spectral differences between the lots including the presence of a crystalline drug fraction in lots which exhibited incomplete dissolution. Solid-state CPMAS 13C-NMR analysis confirmed the presence of a crystalline drug fraction in the problematic capsule lots. Both ATR-IR and CPMAS 13C-NMR spectral results produced a rank ordering of the crystalline drug fraction present in the capsule lots that correspond to the dissolution results.
Markovich
R J
RJ
Department of Physical and Analytical Chemistry Research and Development, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. robert.markovich@spcorp.com
Evans
C A
CA
Coscolluela
C B
CB
Zibas
S A
SA
Rosen
J
J
D000924:Anticholesteremic Agents / Q000032:analysis / Q000737:chemistry*; D001384:Azetidines / Q000032:analysis / Q000737:chemistry*; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004655:Emulsions / Q000032:analysis; D009682:Magnetic Resonance Spectroscopy; D011092:Polyethylene Glycols / Q000737:chemistry*; D012995:Solubility; D013055:Spectrophotometry, Infrared; D014961:X-Ray Diffraction
D000924:Anticholesteremic Agents; D001384:Azetidines; D002214:Capsules; D004655:Emulsions; C095487:1,4-bis(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone; D011092:Polyethylene Glycols