Hausman Debra S, Cambron R Thomas, Sakr Adel
Industrial Pharmacy Graduate Program, College of Pharmacy, University of Cincinnati, 3223 Eden Avenue, Cincinnati, OH 45267, USA.
Int J Pharm. 2005 Aug 11;299(1-2):19-33. doi: 10.1016/j.ijpharm.2005.03.005.
Experiments were conducted to elucidate the relationship between risedronate sodium (RS) hydration state and the physical stability of tablets containing RS. The RS crystal lattice contains channels occupied by water, which is removed by drying processes at temperatures below the boiling point of water, causing a reversible contraction of the crystal lattice. In this study, risedronate sodium was wet granulated followed by fluid bed drying to final granulation moisture contents between 1 and 7%, and then compressed into tablets. During drying, the RS solid-state form was continuously monitored using on-line Raman spectroscopy. Raman spectra acquired in these experiments enabled direct monitoring of changes in the RS crystal lattice, due to dehydration, which provided key information relating RS solid-state form characteristics to final granulation moisture content. Final granulation moisture was found to have a significant effect on the change in RS hydration state measured by Raman spectroscopy. As the final granulation moisture decreased, the amount of RS dehydrated form increased. The largest Raman spectral changes were in the CH stretching region and the region including the 3-picoline ring and PO2- stretches. These changes are indicative of substantial changes in the RS solid-state structure. Final granulation moisture also had a significant effect on the change in tablet thickness over time. Lower final granulation moisture caused a greater increase in tablet thickness as the RS rehydrated. In addition, the change in RS hydration state during fluid bed drying, measured by on-line Raman, was correlated to the increase in tablet thickness and subsequent loss of tablet integrity. Raman spectroscopy allowed direct RS hydration state monitoring, rather than inference from a bulk moisture measurement. Development of a Process Analytical Technology (PAT), specifically Raman, to monitor RS solid-state during drying enabled establishment of relationships between fundamental hydration dynamics associated with RS and final product performance attributes.
进行了实验以阐明利塞膦酸钠（RS）的水合状态与含RS片剂的物理稳定性之间的关系。RS晶格包含被水占据的通道，在低于水沸点的温度下通过干燥过程除去水，导致晶格可逆收缩。在本研究中，将利塞膦酸钠进行湿法制粒，然后通过流化床干燥至最终制粒水分含量在1%至7%之间，然后压制成片剂。在干燥过程中，使用在线拉曼光谱连续监测RS的固态形式。在这些实验中获得的拉曼光谱能够直接监测由于脱水导致的RS晶格变化，这提供了将RS固态形式特征与最终制粒水分含量相关联的关键信息。发现最终制粒水分对通过拉曼光谱测量的RS水合状态变化有显著影响。随着最终制粒水分的降低，RS脱水形式的量增加。最大的拉曼光谱变化发生在CH伸缩区域以及包括3-甲基吡啶环和PO2-伸缩的区域。这些变化表明RS固态结构发生了实质性变化。最终制粒水分对片剂厚度随时间的变化也有显著影响。较低的最终制粒水分导致随着RS再水化片剂厚度增加更大。此外，通过在线拉曼测量的流化床干燥过程中RS水合状态的变化与片剂厚度的增加以及随后片剂完整性的丧失相关。拉曼光谱允许直接监测RS水合状态，而不是从总体水分测量中推断。开发一种过程分析技术（PAT），特别是拉曼光谱，以在干燥过程中监测RS的固态，能够建立与RS相关的基本水合动力学与最终产品性能属性之间的关系。
