title: Crystallinity evaluation of tacrolimus solid dispersions by chemometric analysis.
abstract: Different destructive and nondestructive analytical methods, namely powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), Raman and near-infrared (NIR) spectroscopy and imaging, to detect and characterize tacrolimus trace crystallinity in an amorphous solid dispersion (SD) using chemometric analysis were developed. The SD was spiked with different percentages of the crystalline drug to construct an array of SDs with different crystallinity percentages. Partial least square (PLS) regression analysis was employed to compare the performance of the calibration models created using these analytical methods. The obtained results indicated a significant interaction between tacrolimus and the employed polymer and a drug dissolution dependency on the crystalline fraction within the SDs. Using two PLS factors, these analytical methods were ranked according to its specificity to detect the trace crystallinity of SDs as NIR>PXRD>Raman>DSC. Through the application of PLS, root-mean-squared error of calibration values of 2.91%, 5.36%, 7.07% and 11.58% were calculated for the calibration models constructed by NIR, PXRD, Raman and DSC, respectively. Having a prediction error of 2.1% and a correlation coefficient of 0.99, it is demonstrated that combined NIR imaging and chemometric analysis outperformed the other methods in detecting trace crystallinity in tacrolimus amorphous systems. The spatial distributions of amorphous and crystalline drug were also obtained in order to allow for studying the crystallization dissemination in the solid dispersions. Consequently, NIR and NIR imaging coupled with chemometry was shown to be a powerful tool for the prediction of drug crystallinity within SDs.
authors.affiliation: Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Zidan
authors.forename: Ziyaur
authors.initials: Z
authors.lastname: Rahman
authors.forename: Vilayat
authors.initials: V
authors.lastname: Sayeed
authors.forename: Andre
authors.initials: A
authors.lastname: Raw
authors.forename: Lawrence
authors.initials: L
authors.lastname: Yu
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
mesh_terms: D002138:Calibration; D002152:Calorimetry, Differential Scanning; D002623:Chemistry Techniques, Analytical / Q000592:standards; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D018360:Crystallography, X-Ray; D004304:Dosage Forms; D005079:Excipients / Q000737:chemistry; D065347:Hypromellose Derivatives; D007166:Immunosuppressive Agents / Q000737:chemistry*; D007700:Kinetics; D016018:Least-Squares Analysis; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D008956:Models, Chemical; D033362:Powder Diffraction; D012044:Regression Analysis; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D019265:Spectroscopy, Near-Infrared; D013059:Spectrum Analysis, Raman; D013499:Surface Properties; D016559:Tacrolimus / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods* / Q000592:standards
chemical_list: D004304:Dosage Forms; D005079:Excipients; D007166:Immunosuppressive Agents; D065347:Hypromellose Derivatives; D008747:Methylcellulose; D016559:Tacrolimus