title: Crystalline phase transition of ezetimibe in final product, after packing, promoted by the humidity of excipients: Monitoring and quantification by Raman spectroscopy.
abstract: Ezetimibe (EZT), in its anhydrous form, is a drug used for cholesterol and lipids reduction in blood plasma. The presence of EZT monohydrate in commercial tablets can change the solubility rate of the API, decreasing its activity. The objective of this work was to verify if the humidity present in the excipients could promote the phase transition from EZT anhydrous to hydrate. Initially the stability of the pure anhydrous form was monitored by Raman, at room temperature (23°C) and relative humidity (75%). The MCR-ALS method showed that almost all EZT changed to hydrated form in 30 min. Then tablets of ezetimibe in the presence of its excipients were prepared and vacuum packed using a polyethylene film. Such tablet was monitored by Raman spectroscopy for 24h in order to quantify the mixture of the crystalline forms. A multivariate calibration model using Raman spectroscopy and Partial Least Square (PLS) regression was built, with validation and cross validation errors around 0.6% (wt/wt), for both crystalline forms, and R(2) higher than 0.96. The PLS model was used to quantify the crystalline mixture of ezetimibe in the monitored tablet, after 24h more than 70% of ezetimibe changed to the hydrated form.
authors.affiliation: Department of Chemistry, Federal University of São Carlos, Rodovia Washington Luiz Km 235, 13565-905 São Carlos, SP, Brazil.
authors.forename: Marco Antônio Dos Santos
authors.initials: MADS
authors.lastname: Farias
authors.affiliation: Department of Chemistry, Federal University of São Carlos, Rodovia Washington Luiz Km 235, 13565-905 São Carlos, SP, Brazil.
authors.forename: Frederico Luis Felipe
authors.initials: FLF
authors.lastname: Soares
authors.affiliation: Department of Chemistry, Federal University of São Carlos, Rodovia Washington Luiz Km 235, 13565-905 São Carlos, SP, Brazil. Electronic address: renato.lajarim@ufscar.br.
authors.forename: Renato Lajarim
authors.initials: RL
authors.lastname: Carneiro
mesh_terms: D002138:Calibration; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D000069438:Ezetimibe / Q000737:chemistry*; D006813:Humidity; D016018:Least-Squares Analysis; D044367:Phase Transition; D012995:Solubility; D013059:Spectrum Analysis, Raman / Q000379:methods; D013607:Tablets / Q000737:chemistry; D013696:Temperature
chemical_list: D005079:Excipients; D013607:Tablets; D000069438:Ezetimibe
keywords: Ezetimibe; Multivariate Curve Resolution; Partial Least Squares; Polymorphism; Raman spectroscopy