title: Understanding effect of formulation and manufacturing variables on the critical quality attributes of warfarin sodium product.
abstract: Warfarin sodium (WS) is a narrow therapeutic index drug and its product quality should be thoroughly understood and monitored in order to avoid clinical performance issues. This study was focused on understanding the effect of manufacturing and formulation variables on WS product critical quality attributes (CQAs). Eight formulations were developed with lactose monohydrate (LM) or lactose anhydrous (LA), and were either wet granulated or directly compressed. Formulations were granulated either with ethanol, isopropyl alcohol (IPA) and IPA-water mixture (50:50). Formulations were characterized for IPA, water content, hardness, disintegration time (DT), assay, dissolution and drug physical forms (scanning electron microscopy (SEM), near infrared chemical imaging (NIR-CI), X-ray powder diffraction (XRPD) and solid state nuclear magnetic resonance (ssNMR)), and performed accelerated stability studies at 40°C/75% RH for three days. The DT and dissolution of directly compressed formulations were faster than wet granulated formulations. This was due to phase transformation of crystalline drug into its amorphous form as indicated by SEM, NIR-CI, XRPD and ssNMR data which itself act as a binder. Similarly, LM showed faster disintegration and dissolution than LA containing formulations. Stability results indicated an increase in hardness and DT, and a decrease in dissolution rate and extent. This was due to phase transformation of the drug and consolidation with particles' bonding. In conclusion, the CQAs of WS product were significantly affected by manufacturing and formulation variables.
authors: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA.
authors: Ziyaur
authors: Z
authors: Rahman
authors: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA.
authors: Maxwell
authors: M
authors: Korang-Yeboah
authors: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA.
authors: Akhtar
authors: A
authors: Siddiqui
authors: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA.
authors: Adil
authors: A
authors: Mohammad
authors: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA. Electronic address: Mansoor.Khan@fda.hhs.gov.
authors: Mansoor A
authors: MA
authors: Khan
mesh_terms: D019840:2-Propanol / Q000032:analysis; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D004355:Drug Stability; D011786:Quality Control; D012995:Solubility; D013607:Tablets / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods*; D014859:Warfarin / Q000737:chemistry*; D014867:Water / Q000032:analysis
chemical_list: D013607:Tablets; D014867:Water; D014859:Warfarin; D019840:2-Propanol
keywords: Amorphous; Critical quality attributes; Crystallinity and stability; Disintegration time; Dissolution; Warfarin sodium clathrate