Biopharmaceutics R&D, Bristol-Myers Squibb Company, One Squibb Drive, 105-2-1A, New Brunswick, NJ 08903, USA.
Int J Pharm. 2010 Aug 16;395(1-2):232-5. doi: 10.1016/j.ijpharm.2010.05.033. Epub 2010 May 24.
For an amorphous drug-polymer solid dispersion, a distinctive single T(g) intermediate of the two T(g) values of the two components has been widely considered as an indication of the mixing uniformity, which is critical for the stability of the amorphous drug against crystallization. In this study, two batches of amorphous solid dispersions consisting of BMS-A, a poorly water-soluble drug, and PVP-VA, were made by a twin-screw hot-melt extruder using different processing conditions. Both batches displayed an identical distinctive single T(g) that is consistent with the prediction of Fox equation assuming homogeneous mixing of the two components. Neither DSC nor PXRD detected any drug crystallinity in either batch. However, the two batches exhibited different physical stability against crystallization over time. The application of a Raman mapping method showed that the drug distributed over a much wider concentration range in the less stable solid dispersion. It is therefore experimentally demonstrated that, in the characterization of amorphous solid dispersions, a distinctive single T(g) may not always be a reliable indicator of homogeneity and optimal stability, and more examinations and new techniques may be required other than conventional studies.
对于无定形药物-聚合物固体分散体，两种成分的两个 Tg 值之间的独特单一 Tg 中间相已被广泛认为是混合均匀性的指示，这对于无定形药物抵抗结晶的稳定性至关重要。在这项研究中，使用双螺杆热熔挤出机，通过两种不同的加工条件制备了由 BMS-A（一种水溶性差的药物）和 PVP-VA 组成的两批无定形固体分散体。这两批均显示出相同的独特单一 Tg，与假设两种成分均匀混合的 Fox 方程的预测一致。无论是 DSC 还是 PXRD，在两批样品中均未检测到任何药物结晶度。然而，这两批样品在随时间推移抵抗结晶方面表现出不同的物理稳定性。拉曼映射方法的应用表明，在稳定性较差的固体分散体中，药物的分布浓度范围要宽得多。因此，实验证明，在无定形固体分散体的表征中，独特的单一 Tg 可能并不总是均匀性和最佳稳定性的可靠指标，除了常规研究外，可能还需要进行更多的检查和新技术。
