Development of ezetimibe eutectic with improved biopharmaceutical and mechanical properties to design an optimized oral solid dosage formulation

Abstract

Eutectics are multicomponent systems which are an alternative to the conventional techniques for modulating the biopharmaceutical properties of a pharmaceutical. Ezetimibe (ETZ) is a hypocholesterolemic agent with limited dissolution, poor water solubility, and subsequently demonstrates low oral bioavailability. Additionally, ETZ exhibits poor mechanical properties, leading to difficulties in developing dosage forms through direct compression. The present work highlights the applicability of eutectics in the simultaneous improvement of physicochemical along with mechanical properties of ETZ. A pharmaceutical eutectic of ETZ with succinimide (SUC) was prepared by mechanochemical grinding and thoroughly characterized using thermoanalytical, X-ray diffraction, and spectroscopic methods. Intrinsic dissolution rate and pharmacokinetic analysis were also performed for ezetimibe-succinimide (ETZ-SUC) eutectic in contrast to pure ETZ. The eutectic demonstrated ∼2-fold increase in the solubility and dissolution rate. In pharmacokinetic studies, the area under the curve (AUC) for ETZ-SUC eutectic (28.03 ± 2.22 ng*h/mL) was found to be higher than ETZ (8.98 ± 0.36 ng*h/mL), indicating improved oral bioavailability for eutectics. Also, it was observed that enhanced material functionality aids in designing directly compressed tablets, where the eutectic formulation showed an improved dissolution profile over the ETZ formulation. The study demonstrates that eutectic conglomerates could be utilized to develop ideal oral solid dosage formulations.

Graphical Abstract

Keywords:

• Ezetimibe
• eutectic
• biopharmaceutical properties
• mechanical properties
• oral solid dosage formulation

Acknowledgements

The authors are thankful to MSN Laboratories (Hyderabad, India) for providing the gift sample of Ezetimibe. P.R. and N.P. Acknowledge the financial support received as Institute research fellowship from Birla Institute of Technology, Mesra. The authors sincerely acknowledge the Department of Pharmaceutical Sciences and Technology and CIF facility of BIT Mesra, Ranchi, for providing all the necessary facilities. Authors also thank PK-PD, Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu and Kashmir, India for UPLC-MS/MS facility.

Disclosure statement

The authors report there are no competing interests to declare.

Additional information

Funding

This work was supported by AICTE, Govt. of India, New Delhi under Research Promotion Scheme (RPS) vide F.No. 8-5/RIFD/RPS/Policy-1/2017-18.