title: Chemometric Model Development and Comparison of Raman and (13)C Solid-State Nuclear Magnetic Resonance-Chemometric Methods for Quantification of Crystalline/Amorphous Warfarin Sodium Fraction in the Formulations.
abstract: Warfarin sodium (WS) exists in multiple solid-state forms. The solid-state forms differ in physicochemical properties, and crystalline changes in the drug formulation may influence on the drug product quality and/or clinical performance. It is, therefore, critically important to have a good and reliable analytical method to monitor and quantitate this transformation during stability studies. The aim of the present research was to investigate Raman spectroscopy and solid-state nuclear magnetic resonance ((13)C ssNMR) methods in conjunction with chemometry to quantitate the amorphous and crystalline WS fractions in the drug products. Compositionally identical formulations of amorphous and crystalline WS were prepared, and mixed in various proportions to make 0%-100% amorphous/crystalline sample matrices. Raman and (13)C ssNMR spectra were collected and subjected to partial-least-squares and principle component regressions after mathematical treatment of the data. The model performance parameters such as root-mean-square error of prediction, standard error of prediction, and bias were low for Raman models in comparison to (13)C ssNMR models. Models predicted values of the independent sample matrices match closely with the actual values at high level of crystalline WS. Thus, the developed methods provide means to control and quantitate the WS forms fraction in the drug product.
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, Maryland.
authors.forename: Ziyaur
authors.initials: Z
authors.lastname: Rahman
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, Maryland.
authors.forename: Adil
authors.initials: A
authors.lastname: Mohammad
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, Maryland.
authors.forename: Sohail
authors.initials: S
authors.lastname: Akhtar
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, Maryland.
authors.forename: Akhtar
authors.initials: A
authors.lastname: Siddiqui
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, Maryland.
authors.forename: Maxwell
authors.initials: M
authors.lastname: Korang-Yeboah
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, Maryland.
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
mesh_terms: D000925:Anticoagulants / Q000737:chemistry*; D002138:Calibration; D055598:Chemical Phenomena; D004339:Drug Compounding; D048088:Informatics; D016018:Least-Squares Analysis; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D011208:Powders; D025341:Principal Component Analysis; D011786:Quality Control; D015203:Reproducibility of Results; D019265:Spectroscopy, Near-Infrared; D013059:Spectrum Analysis, Raman; D014859:Warfarin / Q000737:chemistry*
chemical_list: D000925:Anticoagulants; D011208:Powders; D014859:Warfarin
keywords: Raman spectroscopy; amorphous; crystallinity; partial least squares; solid state NMR