Predictions of Onset of Crystallization from Experimental Relaxation Times I-Correlation of Molecular Mobility from Temperatures Above the Glass Transition to Temperatures Below the Glass Transition |
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Authors: | Chandan Bhugra Rama Shmeis Steven L Krill Michael J Pikal |
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Institution: | (1) Department of Pharmaceutical Sciences, School of Pharmacy, U-3092, University of Connecticut, 69 North Eagleville Road, Storrs, Connecticut 06269, USA;(2) Present address: Pharmaceutical Sciences Department, Sanofi-Aventis, 1041, Route 202-206, P.O. Box 6800, Bridgewater, New Jersey 08807-0800, USA;(3) 3 Pharmaceutical R&D, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., P.O. Box 368, Ridgefield, Connecticut 06877, USA |
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Abstract: | Purpose Predicting onsets of crystallization at temperatures below T
g, from data above T
g, would require that the correlation between crystallization onset and mobility is same above and below T
g, and the techniques being used to measure mobility above and below T
g are measuring essentially the same kind of mobility. The aim of this work is to determine if the relaxation times obtained using different techniques (DSC, TAM) below T
g correlate with relaxation time obtained above T
g using dielectric spectroscopy.Methods Model compounds for this work were chosen based on their varied ΔH
f, ΔC
p(T
g) and H-bonding in crystalline state vs. amorphous state. Relaxation times above T
g were determined by the simultaneous fit of real and imaginary permittivity to the Cole-Davidson model. Tau and beta below T
g were determined using isothermal microcalorimetry (TAM) or MDSC. MDSC was used to calculate Kauzmann temperature and strength of the glass using established relationships.Results Indomethacin, nifedipine and flopropione showed Arrhenius temperature dependence throughout the entire temperature range and extrapolation of τ
β
measured above T
g by dielectric relaxation agreed with τ
β
measured below T
g by TAM/MDSC. Ketoconazole, however, showed the expected VTF behavior. For at least two compounds compared (indomethacin and ketoconazole), relaxation times measured by TAM and MDSC did not agree, with TAM giving significantly lower values of τ
β
, but TAM and MDSC relaxation times appeared to extrapolate to a common value at T
g.Conclusions It was found that, for all cases studied, relaxation time constants determined above and below T
g did appear to extrapolate to the same value around T
g indicating that molecular mobility measured above and below T
g using different techniques is highly correlated. |
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Keywords: | amorphous pharmaceuticals calorimetry (DSC) calorimetry (TAM) Cole Davidson model crystallization dielectric relaxation glass transition heat capacity molecular mobility physical stability relaxation time |
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