Polymorphism of 1,2-dihydro-6-neopentyl-2-oxonicotinic acid: characterization, interconversion, and quantitation

Two polymorphs of 1,2-dihydro-6-neopentyl-2-oxonicotinic acid have been characterized by X-ray diffraction (XRD), infrared spectroscopy (IR), differential scanning calorimetry (DSC), and thermal (hot-stage) microscopy (HSM). In batch-scale preparation, form I was crystallized in ethanol-water (3:1), while form II was obtained by recrystallization from acetone-water (2:1). The melting points for forms I and II are 193 and 196 degrees C, respectively. Thermal studies (DSC and HSM) showed that form II melts at 196 degrees C, while form I melts at 193 degrees C, immediately followed by a resolidification and remelt at 196 degrees C. The conversion of form II to form I was accomplished by recrystallization from ethanol or methanol, and the form I-to-form II transition was obtained by controlled heating of form I around 194 degrees C. Quantitative XRD was used to determine the polymorphic composition, with a detection limit of less than 1% of the minor form and a linearity of 0-10% form I in form II (correlation coefficient of 0.999).