De Beer T R M, Vercruysse P, Burggraeve A, Quinten T, Ouyang J, Zhang X, Vervaet C, Remon J P, Baeyens W R G
Laboratory of Pharmaceutical Chemistry and Drug Analysis, Department of Pharmaceutical Analysis, Ghent University, Harelbekestraat 72, B-9000 Gent, Belgium.
J Pharm Sci. 2009 Sep;98(9):3430-46. doi: 10.1002/jps.21633.
The aim of the present study was to examine the complementary properties of Raman and near infrared (NIR) spectroscopy as PAT tools for the fast, noninvasive, nondestructive and in-line process monitoring of a freeze drying process. Therefore, Raman and NIR probes were built in the freeze dryer chamber, allowing simultaneous process monitoring. A 5% (w/v) mannitol solution was used as model for freeze drying. Raman and NIR spectra were continuously collected during freeze drying (one Raman and NIR spectrum/min) and the spectra were analyzed using principal component analysis (PCA) and multivariate curve resolution (MCR). Raman spectroscopy was able to supply information about (i) the mannitol solid state throughout the entire process, (ii) the endpoint of freezing (endpoint of mannitol crystallization), and (iii) several physical and chemical phenomena occurring during the process (onset of ice nucleation, onset of mannitol crystallization). NIR spectroscopy proved to be a more sensitive tool to monitor the critical aspects during drying: (i) endpoint of ice sublimation and (ii) monitoring the release of hydrate water during storage. Furthermore, via NIR spectroscopy some Raman observations were confirmed: start of ice nucleation, end of mannitol crystallization and solid state characteristics of the end product. When Raman and NIR monitoring were performed on the same vial, the Raman signal was saturated during the freezing step caused by reflected NIR light reaching the Raman detector. Therefore, NIR and Raman measurements were done on a different vial. Also the importance of the position of the probes (Raman probe above the vial and NIR probe at the bottom of the sidewall of the vial) in order to obtain all required critical information is outlined. Combining Raman and NIR spectroscopy for the simultaneous monitoring of freeze drying allows monitoring almost all critical freeze drying process aspects. Both techniques do not only complement each other, they also provided mutual confirmation of specific conclusions.
本研究的目的是考察拉曼光谱和近红外（NIR）光谱作为过程分析技术（PAT）工具，用于冷冻干燥过程快速、非侵入性、无损和在线过程监测的互补特性。因此，在冷冻干燥机腔室内安装了拉曼和近红外探头，以便同时进行过程监测。使用5%（w/v）的甘露醇溶液作为冷冻干燥模型。在冷冻干燥过程中连续采集拉曼光谱和近红外光谱（每分钟采集一张拉曼光谱和近红外光谱），并使用主成分分析（PCA）和多元曲线分辨（MCR）对光谱进行分析。拉曼光谱能够提供有关以下方面的信息：（i）整个过程中甘露醇的固态，（ii）冷冻终点（甘露醇结晶终点），以及（iii）过程中发生的几种物理和化学现象（冰核形成起始点、甘露醇结晶起始点）。近红外光谱被证明是监测干燥过程中关键方面的更灵敏工具：（i）冰升华终点，以及（ii）储存期间水合物水的释放监测。此外，通过近红外光谱证实了一些拉曼观察结果：冰核形成起始点、甘露醇结晶终点以及最终产品的固态特性。当在同一个小瓶上进行拉曼和近红外监测时，由于到达拉曼探测器的反射近红外光，在冷冻步骤中拉曼信号会饱和。因此，近红外和拉曼测量是在不同的小瓶上进行的。还概述了探头位置（拉曼探头位于小瓶上方，近红外探头位于小瓶侧壁底部）对于获取所有所需关键信息的重要性。结合拉曼光谱和近红外光谱同时监测冷冻干燥过程，几乎可以监测到冷冻干燥过程的所有关键方面。这两种技术不仅相互补充，还对特定结论提供了相互印证。
