title: Dispersive Raman Spectroscopy for Quantifying Amorphous Drug Content in Intact Tablets.
abstract: 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.
authors.affiliation: Process Analytical Technologies, Merck Manufacturing Division, Merck & Co., Inc., Rahway, New Jersey 07065. Electronic address: busolo.wabuyele@merck.com.
authors.forename: Busolo Wa
authors.initials: BW
authors.lastname: Wabuyele
authors.affiliation: Pharmaceutical Sciences & Clinical Supplies, Merck Research Laboratories, Merck & Co., Inc., West Point, Pennsylvania 19486.
authors.forename: Sutthilug
authors.initials: S
authors.lastname: Sotthivirat
authors.affiliation: Process Analytical Technologies, Merck Manufacturing Division, Merck & Co., Inc., Rahway, New Jersey 07065.
authors.forename: George X
authors.initials: GX
authors.lastname: Zhou
authors.affiliation: Center for Materials Science and Engineering, Merck Manufacturing Division, Merck & Co., Inc., Rahway, New Jersey 07065.
authors.forename: Jason
authors.initials: J
authors.lastname: Ash
authors.affiliation: Pharmaceutical Sciences & Clinical Supplies, Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey 07033.
authors.forename: Sundeep S
authors.initials: SS
authors.lastname: Dhareshwar
mesh_terms: D003460:Crystallization; D016018:Least-Squares Analysis; D009682:Magnetic Resonance Spectroscopy; D015999:Multivariate Analysis; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D013059:Spectrum Analysis, Raman / Q000379:methods*; D013607:Tablets
chemical_list: D004364:Pharmaceutical Preparations; D013607:Tablets
keywords: amorphous quantification; chemometrics; dispersive Raman spectroscopy; multivariate analysis; partial least squares; process-induced amorphization; solid-state NMR