title: Chemometric methods for the quantification of crystalline tacrolimus in solid dispersion by powder X-ray diffractrometry.
abstract: The objective of this study was to develop powder X-ray diffraction (XRPD) chemometric model for quantifying crystalline tacrolimus from solid dispersion (SD). Three SDs (amorphous tacrolimus component) with varying drug to excipient ratios (24.4%, 6.7%, and 4.3% drug) were prepared. Placebo SDs were mixed with crystalline tacrolimus to make their composition equivalent to three SD (crystalline tacrolimus component). These two components were mixed to cover 0%-100% of crystalline drug. Uniformity of the sample mixtures was confirmed by near-infrared chemical imaging. XRPD showed three distinct peaks of crystalline drug at 8.5°, 10.3°, and 11.2° (2θ), which were nonoverlapping with the excipients. Principal component regressions (PCR) and partial least square (PLS) regression used in model development showed high R(2) (>0.99) for all the mixtures. Overall, the model showed low root mean square of standard error, standard error, and bias, which was smaller in PLS than PCR-based model. Furthermore, the model performance was evaluated on the formulations with known percentage of crystalline drug. Model-calculated crystalline drug percentage values were close to actual value. Therefore, these studies strongly suggest the application of chemometric-XRPD models as a quality control tool to quantitatively predict the crystalline drug in the formulation.
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, OPS, CDER, United States Food and Drug Administration.
authors.forename: Akhtar
authors.initials: A
authors.lastname: Siddiqui
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, OPS, CDER, United States Food and Drug Administration.
authors.forename: Ziyaur
authors.initials: Z
authors.lastname: Rahman
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, OPS, CDER, United States Food and Drug Administration.
authors.forename: Srikant
authors.initials: S
authors.lastname: Bykadi
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, OPS, CDER, United States Food and Drug Administration. Electronic address: Mansoor.Khan@fda.hhs.gov.
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization / Q000379:methods; D005079:Excipients / Q000737:chemistry; D016018:Least-Squares Analysis; D033362:Powder Diffraction / Q000379:methods; D011208:Powders / Q000737:chemistry*; D025341:Principal Component Analysis; D019265:Spectroscopy, Near-Infrared / Q000379:methods; D016559:Tacrolimus / Q000737:chemistry*; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D005079:Excipients; D011208:Powders; D016559:Tacrolimus
keywords: chemometric; multivariate analysis; partial least square; powder X-ray diffraction; principal component analysis; solid dispersion; tacrolimus