title: Determination of tacrolimus crystalline fraction in the commercial immediate release amorphous solid dispersion products by a standardized X-ray powder diffraction method with chemometrics.
abstract: Clinical performance of an amorphous solid dispersion (ASD) drug product is related to the amorphous drug content because of the greater bioavailability of this form of the drug than its crystalline form. Therefore, it is paramount to monitor the amorphous and the crystalline fractions in the ASD products. The objective of the present investigation was to study the feasibility of using a standardized X-ray powder diffraction (XRPD) in conjunction with chemometric methods to quantitate the amorphous and crystalline fraction of the drug in several tacrolimus ASD products. Three ASD products were prepared in which drug to excipients ratios ranged from 1:19 to 1:49. The amorphous and crystalline drug products were mixed in various proportions so that amorphous/crystalline tacrolimus in the samples vary from 0 to 100%. XRPD of the samples of the drug products were collected, and PLSR and PCR chemometric methods were applied to the data. The R(2) was greater than '0.987' for all the models and bias in the models were statistically insignificant (p>0.05). RMSEP and SEP values were smaller for PLSR models than PCR models. The models prediction capabilities were good and can predict as low as 10% when drug to excipient ratio is as high as 1:49. In summary, XRPD and chemometric provide powerful analytical tools to monitor the crystalline fractions of the drug in the ASD products.
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA.
authors.forename: Ziyaur
authors.initials: Z
authors.lastname: Rahman
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA.
authors.forename: Akhtar
authors.initials: A
authors.lastname: Siddiqui
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA.
authors.forename: Srikant
authors.initials: S
authors.lastname: Bykadi
authors.affiliation: 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.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D065546:Drug Liberation; D025341:Principal Component Analysis; D012995:Solubility; D016559:Tacrolimus / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D016559:Tacrolimus
keywords: Amorphous solid dispersion; Partial least square regression; Principle component regression; Tacrolimus; X-ray powder diffraction