Pharmaceutical Engineering Group, School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
Pharmaceutical Engineering Group, School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
Int J Pharm. 2019 Jul 20;566:476-487. doi: 10.1016/j.ijpharm.2019.05.029. Epub 2019 May 11.
Currently in the pharmaceutical industry, continuous manufacturing is an area of significant interest. In particular, hot-melt extrusion (HME) offers many advantages and has been shown to significantly reduce the number of processing steps relative to a conventional product manufacturing line. To control product quality during HME without process interruption, integration of inline analytical technology is critical. Vibrational spectroscopy (Raman, NIR and FT-IR) is often employed and used for real-time measurements because of the non-destructive and rapid nature of these analytical techniques. However, the establishment of reliable Process Analytical Technology (PAT) tools for HME of thermolabile drugs is challenging. Indeed, the Raman effect is inherently weak and might be subject to interference. Moreover, during HME, heating and photodecomposition can occur and disrupt spectra acquisition. The aim of this research article was to explore the use of inline Raman spectroscopy to characterise a thermolabile drug, ramipril (RMP), during continuous HME processing. Offline measurements by HPLC, LC-MS and Raman spectroscopy were used to characterise RMP and its main degradation product, ramipril-diketopiperazine (RMP-DKP, impurity K). A set of HME experiments together with inline Raman spectroscopic analyses were performed. The feasibility of implementing inline Raman spectroscopic analysis to quantify the level of RMP and RMP-DKP in the extrudate was addressed. Two regions in the Raman spectrum were selected to differentiate RMP and RMP-DKP. When regions were combined, a principle component analysis (PCA) model defined by these two main components (PC 1 = 50.1% and PC 2 = 45%) was established. Using HPLC analyses, we were able to confirm that the PC 1 score was attributed to the level of RMP-DKP, and the PC 2 score was related to the RMP drug content. Investigation of the PCA scatterplot indicated that HME processing temperature was not the only factor causing RMP degradation. Additionally, the plasticiser content, feeding speed and screw rotating speed contributed to RMP degradation during HME processing.
目前，在制药行业中，连续制造是一个备受关注的领域。特别是热熔挤出（HME）具有许多优势，与传统的产品制造工艺相比，它显著减少了加工步骤的数量。为了在不中断工艺的情况下控制 HME 过程中的产品质量，集成在线分析技术至关重要。振动光谱（拉曼、近红外和傅里叶变换红外）由于这些分析技术具有非破坏性和快速的特点，因此经常被用于实时测量。然而，建立可靠的热不稳定药物 HME 的过程分析技术（PAT）工具具有挑战性。实际上，拉曼效应本质上很微弱，可能会受到干扰。此外，在 HME 过程中，加热和光分解可能会发生，从而破坏光谱采集。本文的目的是探讨在线拉曼光谱在热敏药物雷米普利（RMP）连续 HME 加工过程中的应用。通过高效液相色谱法（HPLC）、液质联用（LC-MS）和拉曼光谱对 RMP 及其主要降解产物雷米普利二酮哌嗪（RMP-DKP，杂质 K）进行了离线测量。进行了一组 HME 实验和在线拉曼光谱分析。探讨了实施在线拉曼光谱分析来定量测定挤出物中 RMP 和 RMP-DKP 水平的可行性。在拉曼光谱中选择了两个区域来区分 RMP 和 RMP-DKP。当区域结合时，建立了一个由这两个主要成分（PC1=50.1%和 PC2=45%）定义的主成分分析（PCA）模型。使用高效液相色谱分析，我们能够确认 PC1 得分归因于 RMP-DKP 的水平，而 PC2 得分与 RMP 药物含量有关。对 PCA 散点图的研究表明，HME 加工温度并不是导致 RMP 降解的唯一因素。此外，增塑剂含量、进料速度和螺杆转速都会导致 RMP 在 HME 加工过程中降解。
