Characterization of amorphous ketoconazole using modulated temperature differential scanning calorimetry

The objective of the present study was to characterize the glassy state of ketoconazole and to calculate its molecular mobility below the glass transi tion, with a view to further developing the use of modulated temperature di fferential scanning calorimetry (MTDSC) as a means of studying relaxation b ehavior. Particular emphasis is placed on identifying the influence of the choice of experimental parameters on the measured values of both the glass transition temperature (T-g) and the relaxation enthalpy magnitude. Amorpho us ketoconazole was studied using an amplitude of +/-0.212 K, a period of 4 0 s, and an underlying heating rate of 2 K/min. The correction required for the calculation of the relaxation endotherm magnitude (the 'T-g shift effe ct') was demonstrated and is discussed in terms of the mechanism underpinni ng this phenomenon. Similarly, the influence of the choice of MTDSC experim ental parameters on the measured T-g was studied by varying the amplitude f rom +/-0.011 to +/-0.424 K and the period from 25 to 50 s. The influence of the cooling rate from the melt on the magnitude of the relaxation endother m and position of the glass transition was investigated. It was noted that the magnitude of the relaxation endotherm increased with slower cooling rat es, this being ascribed to a combination of annealing during the cooling an d heating cycle and a further facet of the T-g shift effect. Annealing expe riments were performed at aging temperatures T-g-12-T-g-42 K for periods ra nging from 10 min up to 16 h. The relaxation behavior was characterized by fitting the calculated extent of relaxation to the Williams-Watts equation. Overall, the study has highlighted theoretical and experimental issues tha t need to be considered when using both DSC and MTDSC for the calculation o f relaxation times. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutic al Association.