title: Development and validation of X-ray diffraction method for quantitative determination of crystallinity in warfarin sodium products.
abstract: The objective of this study was to develop and validate XRPD analytical method for the estimation of percent crystalline warfarin sodium present in drug products. Warfarin sodium (WS) is a clathrate containing Isopropyl alcohol entrapped in the crystalline structure. Four types of WS-excipient mixtures were prepared and used to make four formulations: M1 containing lactose monohydrate (WS: excipient 1:9), M2 containing anhydrous lactose (WS: excipient 1:9), M3 containing lactose monohydrate (WS: excipient 1:21.5), M4 containing lactose anhydrous (WS: excipient 1:21.5). Thoroughly mixed powders were packed in the XRD sample holders and diffractogram were collected. Diffractogram in the 7-9 2θ were found to be distinctive as the peak intensity grows with increasing percent crystalline WS. This peak region was, therefore, used to validate the XRPD method. Validation parameters were evaluated for accuracy, precision, linearity, limit of detection (LOD), and limit of quantitation (LOQ). LOD and LOQ for M1, M2, M3, and M4 were 3.04, 3.17, 4.17, 4.49% and 9.21, 9.62, 12.65, 13.30%, respectively. The method was found to be linear with R(2)>0.99. With changing scan speed, X-ray power output, and type of sample holder, the method was found to be robust. Prediction of the % crystalline content of the WS sample with known crystallinity showed close agreement between actual and predicted value. In summary, XRPD method was validated, which can be used as a quantitative method for the estimation of % crystalline WS present in a drug product.
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, OPS, CDER, FDA, United States.
authors.forename: Akhtar
authors.initials: A
authors.lastname: Siddiqui
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, OPS, CDER, FDA, United States.
authors.forename: Ziyaur
authors.initials: Z
authors.lastname: Rahman
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, OPS, CDER, FDA, United States.
authors.forename: Maxwell
authors.initials: M
authors.lastname: Korang-Yeboah
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, OPS, CDER, FDA, United States. Electronic address: Mansoor.Khan@fda.hhs.gov.
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
mesh_terms: D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D005079:Excipients / Q000737:chemistry; D011208:Powders / Q000737:chemistry*; D015203:Reproducibility of Results; D014859:Warfarin / Q000737:chemistry*; D014961:X-Ray Diffraction / Q000379:methods*
chemical_list: D005079:Excipients; D011208:Powders; D014859:Warfarin
keywords: Amorphous; Analytical method; Quality control; Validation; Warfarin; XRPD