Dispersive Raman Spectroscopy for Quantifying Amorphous Drug Content in Intact Tablets

详细信息    查看全文

• 作者：Busolo Wa Wabuyele¹ ; ^{busolo.wabuyele@merck.com} ; Sutthilug Sotthivirat² ; George X. Zhou¹ ; Jason Ash³ ; Sundeep S. Dhareshwar⁴
• 关键词：process-induced amorphization ; amorphous quantification ; dispersive Raman spectroscopy ; chemometrics ; multivariate analysis ; partial least squares ; solid-state NMR
• 刊名：Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：106
• 期：2
• 页码：579-588
• 全文大小：1256 K
• 卷排序：106

文摘

Process-induced inadvertent phase change of an active pharmaceutical ingredient in a drug product could impact chemical stability, physical stability, shelf life, and bioperformance. In this study, dispersive Raman spectroscopy is presented as an alternative method for the nondestructive, high-throughput, at-line quantification of amorphous conversion. A quantitative Raman method was developed using a multivariate partial least squares (PLS) regression calibration technique with solid-state nuclear magnetic resonance (ssNMR) spectroscopy as the reference method. Compositionally identical calibration tablets containing 20% w/w total MK-A drug in varying weight proportions (0%-50% w/w based on total MK-A) of amorphous and crystalline MK-A were compressed at 10-45 kN force. PLS predictions of amorphous content of tablets using Raman spectroscopy correlated well with ssNMR quantification. The predictive accuracy of this model led to a strong correlation (R2 = 0.987) with a root mean-squared error of prediction of 1.5% w/w amorphous MK-A in tablets up to 50% w/w amorphous conversion in compressive stress range of 60-320 MPa. Overall, these results suggest that dispersive Raman spectroscopy offers fast, sensitive, and high-throughput (<5 min/tablet) method for quantitating amorphous conversion.