TY - JOUR
T1 - The development of modulated, quasi-isothermal and ultraslow thermal methods as a means of characterizing the α to γ indomethacin polymorphic transformation
AU - Qi, Sheng
AU - Craig, Duncan
PY - 2012
Y1 - 2012
N2 - While polymorphism remains a key issue within the pharmaceutical and related industries, the understanding of the transformation process itself remains relatively poorly understood. In this study we use a combination of conventional and modulated temperature differential scanning calorimetry (MTDSC), quasi-isothermal MTDSC (Qi-MTDSC) and ultraslow heating rate MTDSC as a novel means of investigating the temperature-induced α to γ transformation in indomethacin, using hot stage microscopy and variable temperature attenuated total reflectance FTIR spectroscopy as supportive techniques. In particular, we utilize the ability of MTDSC to measure subtle heat capacity changes through the transformation, we examine the use of Lissajous analysis of the modulated heating signal itself (both scanning and quasi-isothermal) and finally we investigate the use of ultraslow heating rates (down to 0.04 °C/min) so as to facilitate examination of the melt-crystallization process at a scanning rate whereby kinetic hindrance becomes negligible. Indomethacin was prepared in the metastable α and stable γ forms using standard approaches. Samples were studied using conventional DSC, Qi-MTDSC (involving holding and modulating the sample at a series of incremental temperature steps) and ultraslow MTDSC. All studies were conducted using a Q-1000 MTDSC using crimped pans, following standard calibration procedures. Conventional DSC at 10 °C/min showed the expected single melting responses for the α and γ forms, while MTDSC at slower rates indicated the presence of a melt-crystallization process. Quasi-isothermal studies allowed the heat capacity to be estimated as a function of time, while the associated Lissajous analysis demonstrated distortion of the elliptical response as a result of the kinetic events involved. Ultraslow heating resulted in superimposition of the melting and crystallization processes, resulting in a discrete thermal event that was enthalpically equivalent to the difference between the two processes. It is suggested that these combined thermal methods allow the conversion to be profiled in a manner which facilitates both kinetic and thermodynamic analysis of the transformation.
AB - While polymorphism remains a key issue within the pharmaceutical and related industries, the understanding of the transformation process itself remains relatively poorly understood. In this study we use a combination of conventional and modulated temperature differential scanning calorimetry (MTDSC), quasi-isothermal MTDSC (Qi-MTDSC) and ultraslow heating rate MTDSC as a novel means of investigating the temperature-induced α to γ transformation in indomethacin, using hot stage microscopy and variable temperature attenuated total reflectance FTIR spectroscopy as supportive techniques. In particular, we utilize the ability of MTDSC to measure subtle heat capacity changes through the transformation, we examine the use of Lissajous analysis of the modulated heating signal itself (both scanning and quasi-isothermal) and finally we investigate the use of ultraslow heating rates (down to 0.04 °C/min) so as to facilitate examination of the melt-crystallization process at a scanning rate whereby kinetic hindrance becomes negligible. Indomethacin was prepared in the metastable α and stable γ forms using standard approaches. Samples were studied using conventional DSC, Qi-MTDSC (involving holding and modulating the sample at a series of incremental temperature steps) and ultraslow MTDSC. All studies were conducted using a Q-1000 MTDSC using crimped pans, following standard calibration procedures. Conventional DSC at 10 °C/min showed the expected single melting responses for the α and γ forms, while MTDSC at slower rates indicated the presence of a melt-crystallization process. Quasi-isothermal studies allowed the heat capacity to be estimated as a function of time, while the associated Lissajous analysis demonstrated distortion of the elliptical response as a result of the kinetic events involved. Ultraslow heating resulted in superimposition of the melting and crystallization processes, resulting in a discrete thermal event that was enthalpically equivalent to the difference between the two processes. It is suggested that these combined thermal methods allow the conversion to be profiled in a manner which facilitates both kinetic and thermodynamic analysis of the transformation.
U2 - 10.1021/mp2003412
DO - 10.1021/mp2003412
M3 - Article
VL - 9
SP - 1087
EP - 1099
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 5
ER -