Monteyne Tinne, Heeze Liza, Oldörp Klaus, Vervaet Chris, Remon Jean-Paul, De Beer Thomas
Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
Center for Material Characterization of Products, Thermo Fisher, Dieselstrasse 4, 76227 Karlsruhe, Germany.
Eur J Pharm Biopharm. 2016 Jun;103:127-135. doi: 10.1016/j.ejpb.2016.03.030. Epub 2016 Apr 1.
Twin screw hot melt granulation (TSHMG) is an innovative and continuous drug formulation process allowing granulation of moisture sensitive drugs. However, due to the lack of experience and in-depth process understanding, this technique is not yet widely used. During the TSHMG process, the microstructure of the granules is generated and modified and strongly depends on the flow behavior of the material. Hence, rheology might be a suitable tool to simulate and examine this process. However, chemical interactions of the material are influencing the physical properties leading to the microstructure. In this research project it is spectroscopically investigated whether the heat applied in a rheometer induces the same molecular effects as these occurring during TSHMG of the model formulation caffeine anhydrous/Soluplus®. Hence, it is evaluated whether rheology can be used as a simulation tool to improve the understanding of the material behavior at molecular level during continuous melt granulation. Therefore, in-line Raman spectroscopy is executed during TSHMG and in situ Fourier Transform Infra-red (FTIR) during oscillatory rheological experiments. The results from the in-line Raman monitoring revealed polymorph transition of caffeine anhydrous during twin screw melt granulation with Soluplus® which is stimulated depending on the binder concentration and/or granulation temperature. A correlation was seen between the FTIR spectra obtained during the rheological temperature ramp and the in-line collected Raman spectra during the melt granulation runs. The polymorphic conversion of caffeine anhydrous could be detected in the same temperature range with both techniques, proving the comparability of plate-plate rheometry and hot melt granulation (HMG) for this case with the used parameter settings. Process simulation using rheology combined with in situ FTIR seems a promising approach to increase process understanding and to facilitate binder and parameter selection for TSHMG.
双螺杆热熔制粒（TSHMG）是一种创新的连续药物制剂工艺，可用于对湿度敏感药物进行制粒。然而，由于缺乏经验和对工艺的深入理解，该技术尚未得到广泛应用。在TSHMG过程中，颗粒的微观结构会生成并发生改变，且很大程度上取决于物料的流动行为。因此，流变学可能是模拟和研究此过程的合适工具。然而，物料的化学相互作用会影响导致微观结构形成的物理性质。在本研究项目中，通过光谱学方法研究了流变仪中施加的热量是否会引发与无水咖啡因/Soluplus®模型制剂TSHMG过程中相同的分子效应。因此，评估了流变学是否可用作模拟工具，以增进对连续熔融制粒过程中分子水平上物料行为的理解。为此，在TSHMG过程中进行在线拉曼光谱分析，并在振荡流变实验中进行原位傅里叶变换红外（FTIR）分析。在线拉曼监测结果显示，在与Soluplus®进行双螺杆熔融制粒过程中，无水咖啡因发生了多晶型转变，这种转变受粘合剂浓度和/或制粒温度的影响。流变温度斜坡过程中获得的FTIR光谱与熔融制粒过程中在线采集的拉曼光谱之间存在相关性。两种技术均可在相同温度范围内检测到无水咖啡因的多晶型转变，证明了在本案例所使用的参数设置下，平板流变仪和热熔制粒（HMG）具有可比性。结合原位FTIR使用流变学进行过程模拟似乎是一种很有前景的方法，可用于增进对过程的理解，并有助于为TSHMG选择粘合剂和参数。
