title: Comparison of X-ray powder diffraction and solid-state nuclear magnetic resonance in estimating crystalline fraction of tacrolimus in sustained-release amorphous solid dispersion and development of discriminating dissolution method.
abstract: The focus of present investigation was to explore X-ray powder diffraction (XRPD) and solid-state nuclear magnetic resonance (ssNMR) techniques for amorphous and crystalline tacrolimus quantification in the sustained-release amorphous solid dispersion (ASD), and to propose discriminating dissolution method that can detect crystalline drug. The ASD and crystalline physical mixture was mixed in various proportions to make sample matrices containing 0%-100% crystalline-amorphous tacrolimus. Partial-least-square regression and principle component regression were applied to the spectral data. Dissolution of the ASD in the US FDA recommended dissolution medium with and without surfactant was performed. R(2) > 0.99 and slope was close to one for all the models. Root-mean-square of prediction, standard error of prediction, and bias were higher in ssNMR-based models when compared with XRPD data models. Dissolution of the ASD decreased with an increase in the crystalline tacrolimus in the formulations. Furthermore, detection of crystalline tacrolimus in the ASD was progressively masked with an increase in the surfactant level in the dissolution medium. XRPD and ssNMR can be used equally to quantitate the crystalline and amorphous fraction of tacrolimus in the ASD with good accuracy; however, ssNMR data collection time is excessively long, and minimum surfactant level in the dissolution medium maximizes detection of crystalline reversion in the formulation.
authors.affiliation: Division of Product Quality and Research, office of Testing and Research, Center for Drug Evaluation and Research, Food and Drug Administration, Maryland.
authors.forename: Ziyaur
authors.initials: Z
authors.lastname: Rahman
authors.forename: Srikant
authors.initials: S
authors.lastname: Bykadi
authors.forename: Akhtar
authors.initials: A
authors.lastname: Siddiqui
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
mesh_terms: D003460:Crystallization; D003692:Delayed-Action Preparations; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D033362:Powder Diffraction / Q000379:methods*; D012995:Solubility; D016559:Tacrolimus / Q000032:analysis* / Q000737:chemistry*; D014961:X-Ray Diffraction / Q000379:methods*
chemical_list: D003692:Delayed-Action Preparations; D016559:Tacrolimus
keywords: X-ray powder diffractometry; dissolution; partial least squares; principal component analysis; solid dispersion; solid state NMR