Arnfast Lærke, van Renterghem Jeroen, Aho Johanna, Bøtker Johan, Raijada Dhara, Baldursdóttir Stefania, De Beer Thomas, Rantanen Jukka
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
Pharmaceutics. 2020 Feb 1;12(2):116. doi: 10.3390/pharmaceutics12020116.
The specific aim in this study was to understand the effect of critical process parameters on the solid form composition of model drug compounds during hot melt extrusion using in-line Raman spectroscopy combined with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) modeling for semi-quantitative kinetic profiling. It was observed that the hydrate and anhydrate solid forms of two model drugs in the melts of nitrofurantoin (NF):polyethylene oxide (PEO) and piroxicam (PRX):PEO could be resolved from a MCR-ALS model without an external calibration dataset. Based on this model, the influence of two critical process parameters (shear and temperature) on the solid form composition could be evaluated in a real-time mode and the kinetics of complex transformation pathways could be explored. Additionally, the dehydration pathways of NF monohydrate and PRX monohydrate in molten PEO could be derived. It can be concluded that dehydration of both hydrates in PEO occurs via competing mechanisms-a solution-mediated transformation pathway and a solid-solid transformation, and that the balance between these mechanisms is determined by the combined effect of both temperature and shear. Another important observation was that the water released from these hydrate compounds has a detectable effect on the rheological characteristics of this mixture.
本研究的具体目的是，通过在线拉曼光谱结合多元曲线分辨-交替最小二乘法（MCR-ALS）建模进行半定量动力学分析，来了解热熔挤出过程中关键工艺参数对模型药物化合物固体形态组成的影响。结果发现，对于呋喃妥因（NF）：聚环氧乙烷（PEO）和吡罗昔康（PRX）：PEO熔体中的两种模型药物，无需外部校准数据集，就能从MCR-ALS模型中分辨出水合物和无水物固体形态。基于该模型，可以实时评估两个关键工艺参数（剪切力和温度）对固体形态组成的影响，并探索复杂转变途径的动力学。此外，还可以推导NF一水合物和PRX一水合物在熔融PEO中的脱水途径。可以得出结论，PEO中两种水合物的脱水是通过竞争机制发生的——溶液介导的转变途径和固-固转变，这些机制之间的平衡由温度和剪切力的综合作用决定。另一个重要发现是，这些水合物化合物释放出的水对该混合物的流变特性有可检测到的影响。
