Bhugra Chandan, Shmeis Rama, Krill Steven L, Pikal Michael J
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA.
J Pharm Sci. 2008 Jan;97(1):455-72. doi: 10.1002/jps.21162.
Given a good correlation between onsets of crystallization and mobility above T(g), one might be able to predict crystallization onsets at a temperature of interest far below T(g) from this correlation and measurement of mobility at a temperature below T(g). Such predictions require that: (a) correlation between crystallization onset and mobility is the same above and below T(g), and (b) techniques used to measure mobility above and below T(g) measure the same kind of mobility [(b) demonstrated previously using dielectric and calorimetric techniques]. The objective of present work is to determine whether crystallization onset times couple with relaxation times determined above T(g), and if so to verify predictions made below T(g) (from data above T(g)) with experimental data. Model compounds were indomethacin, ketoconazole, flopropione, nifedipine, and felodipine. Onsets of crystallization measured above T(g) were coupled with dielectric mobility for indomethacin, felodipine, and flopropione. Prediction of crystallization onset times for temperatures below T(g) matched well with experimental data for indomethacin (25 degrees C, 35 degrees C: Predicted 473, 95 h;
624 +/- 158, 139 +/- 49 h) and flopropione (35 degrees C, 40 degrees C; Predicted 115, 58 h;
96 +/- 30, 59 +/- 10 h). The data suggests that coupling between crystallization onsets and molecular mobility at temperatures above T(g) may be exploited to develop stability testing protocol for crystallization from amorphous state.
鉴于结晶开始与高于玻璃化转变温度（T(g)）时的流动性之间具有良好的相关性，人们或许能够根据这种相关性以及在低于T(g)的温度下对流动性的测量，预测在远低于T(g)的感兴趣温度下的结晶开始情况。此类预测要求：(a) 高于和低于T(g)时，结晶开始与流动性之间的相关性相同；以及(b) 用于测量高于和低于T(g)时流动性的技术测量的是同一种流动性 [先前已使用介电和量热技术证明了(b)]。本研究的目的是确定结晶开始时间是否与在T(g)以上确定的弛豫时间相关联，如果是，则用实验数据验证在低于T(g)时（根据高于T(g)的数据）所做的预测。模型化合物为吲哚美辛、酮康唑、氟丙酰、硝苯地平和非洛地平。在T(g)以上测量的结晶开始与吲哚美辛、非洛地平和氟丙酰的介电流动性相关联。对于低于T(g)的温度下的结晶开始时间的预测与吲哚美辛（25℃、35℃：预测值473、95小时；实验值：624±158、139±49小时）和氟丙酰（35℃、40℃；预测值115、58小时；实验值：96±30、59±10小时）的实验数据匹配良好。数据表明，高于T(g)的温度下结晶开始与分子流动性之间的关联可用于开发从非晶态结晶的稳定性测试方案。
