A simple quantitative FT-IR approach for the study of a polymorphic transformation under crystallization slurry conditions.
The pharmaceutical compound (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine hydrochloride (denoted here as Compound X), has been found to crystallize in at least two polymorphic forms. Using only two frequencies (1009 and 1058 cm(-1)) in the infrared, a linear (R=0.998) calibration plot, consisting of the ratio of the peak absorbances plotted against polymorph concentration, was constructed. This plot allowed the quantification of binary mixtures of polymorphs ranging from <3 to approximately 100 wt% Form II in Form I. Spectra were acquired in transmission mode using mineral oil (Nujol) mull sample preparation, for reasons of compatibility with wet cake and slurry samples. The transformation of the less thermodynamically stable polymorph (Form II) to the more stable form (Form I), in stirred methyl isobutyl ketone (MIBK) slurries, was monitored spectroscopically as a function of time. Performing the experiment at various temperatures allowed the energy of activation for the process to be estimated (42 kJ/mol).
Skrdla
P J
PJ
Merck & Co., Inc., P. O. Box 2000, Rahway, NJ 07065, USA. peter_skrdla@merck.com
Antonucci
V
V
Crocker
L S
LS
Wenslow
R M
RM
Wright
L
L
Zhou
G
G
D003460:Crystallization; D009025:Morpholines / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods*; D013816:Thermodynamics
C435717:2-((1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-3-(4-fluorophenyl)morpholine; D009025:Morpholines