Pharmaceutical Engineering Group, School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, United Kingdom; China Medical University - Queen's University Belfast joint College (CQC), No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, PR China.
Pharmaceutical Engineering Group, School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, United Kingdom.
Int J Pharm. 2021 Jan 5;592:120024. doi: 10.1016/j.ijpharm.2020.120024. Epub 2020 Oct 29.
Complications associated with uncontrolled hypertension are considered the major cause of premature death worldwide. Fixed-dose combinations (FDCs) offer an alternative approach to polypharmacy with the aim to improve patient compliance. Process Analytical Technology (PAT) is gaining momentum as a non-invasive, predictive tool to control the quality of drugs during continuous processing. PAT offers real-time quality control that can be built into the production line. However, the vast majority of studies reported in the literature have focused on quantifying a single drug during continuous processing. The aim of this study was to develop non-destructive, predictive inline PAT tools allowing for the simultaneous quantification of two antihypertensive drugs, Hydrochlorothiazide (HCTZ) and Ramipril (RMP), during the continuous manufacture of FDCs. A calibration set composed of HCTZ and RMP at concentration ranges of 6.5 to 40 and 2.5-15 (% w/w), respectively, were manufactured using hot melt extrusion. The extrudates were analysed during the process using inline Raman spectroscopy. Optimum wavenumber regions were observed at 200-400 and 630-730 cm for HCTZ, and 980-1100 cm for RMP using principal component analysis. Partial least squares (PLS) regression was performed to establish the predictive calibration models. The PLS developed models showed excellent linearity (R2 = 0.986 and 0.974), selectivity (PC1 = 98.6% and 91.9%) and accuracy (RMSEcv = 1.586 and 0.645%) for HCTZ and RMP, respectively. Additionally, RMSEP values were reported as 1.237 and 1.007% for HCTZ and RMP, respectively, depicting good predictability for drug content in the validation set. The output of this study demonstrated that utilisation of the full potential of chemometrics, Raman spectroscopy can be used for the simultaneous inline quantification of multiple drugs in complex formulations. This facilitates the in-process quality control of FDCs and other multicomponent systems during continuous pharmaceutical production.
与未控制的高血压相关的并发症被认为是全球范围内导致过早死亡的主要原因。固定剂量组合（FDC）提供了一种替代多药治疗的方法，旨在提高患者的依从性。过程分析技术（PAT）作为一种非侵入性、预测性工具，正在获得发展动力，用于控制连续处理过程中的药物质量。PAT 提供实时质量控制，可以集成到生产线中。然而，文献中报道的绝大多数研究都集中在连续处理过程中对单一药物进行定量。本研究的目的是开发非破坏性的、预测性的在线 PAT 工具，允许同时定量两种降压药物氢氯噻嗪（HCTZ）和雷米普利（RMP），用于 FDC 的连续制造。使用热熔挤出法制造浓度范围分别为 6.5 至 40 和 2.5 至 15（%w/w）的 HCTZ 和 RMP 的校准集。使用在线拉曼光谱法在过程中分析挤出物。使用主成分分析（PCA）观察到 HCTZ 的最佳波数区域为 200-400 和 630-730cm，RMP 的最佳波数区域为 980-1100cm。进行偏最小二乘（PLS）回归以建立预测校准模型。所开发的 PLS 模型显示出极好的线性（R2=0.986 和 0.974）、选择性（PC1=98.6%和 91.9%）和准确性（RMSEcv=1.586 和 0.645%），分别用于 HCTZ 和 RMP。此外，HCTZ 和 RMP 的 RMSEP 值分别报告为 1.237%和 1.007%，表明对验证集中药物含量具有良好的预测能力。本研究的结果表明，充分利用化学计量学的潜力，拉曼光谱可用于复杂配方中多种药物的同时在线定量。这有助于在连续制药生产过程中对 FDC 和其他多组分系统进行过程质量控制。
