Crystalline phase transition of ezetimibe in final product, after packing, promoted by the humidity of excipients: Monitoring and quantification by Raman spectroscopy

• Pure ezetimibe anhydrous suffered fast solvatomorphic transition.
• PLS models allowed the quantification of ezetimibe forms among its excipients.
• The quantification models presented RMSEV between 5.6–6.4% for all components.
• Most of the anhydrous ezetimibe suffered hydration in the tablets.

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 24 h 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 R2 higher than 0.96. The PLS model was used to quantify the crystalline mixture of ezetimibe in the monitored tablet, after 24 h more than 70% of ezetimibe changed to the hydrated form.

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