Effect of Differential Surface Anisotropy on Dissolution Behavior of Fenofibrate Crystal Habits: Comparative Study using USP Type 2 and Type 4 Dissolution Apparatuses

Sakshi M Shah; Soumalya Chakraborty; Gurudutt Dubey; Suhas Yewale; Rohit Y Sathe; L Ramaswamy; Samir Haddouchi; Vijay Thiruvenkatam; Prasad V Bharatam; Arvind K Bansal

doi:10.1016/j.xphs.2024.02.001

Effect of Differential Surface Anisotropy on Dissolution Behavior of Fenofibrate Crystal Habits: Comparative Study using USP Type 2 and Type 4 Dissolution Apparatuses

J Pharm Sci. 2024 Feb 8:S0022-3549(24)00044-3. doi: 10.1016/j.xphs.2024.02.001. Online ahead of print.

Authors

Affiliations

¹ Solid State Pharmaceutics Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
² Department of Chemistry, Indian Institute of Technology (IIT), Gandhinagar, Palaj, Gujarat 382355, India.
³ Sotax India Pvt. Ltd., Mumbai, Maharashtra 400063, India.
⁴ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
⁵ SPS Pharma Services, Orléans, France.
⁶ Solid State Pharmaceutics Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India. Electronic address: akbansal@niper.ac.in.

PMID: 38336008
DOI: 10.1016/j.xphs.2024.02.001

Abstract

The solid-state properties of active pharmaceutical ingredient (API) have significant impact on its dissolution performance. In the present study, two different crystal habits viz. rod and plate shape of form I of FEN were evaluated for dissolution profile using USP Type 2 and Type 4 apparatuses. Molecular basis of differential dissolution performance of different crystal habits was investigated. Rod (FEN-R) and plate (FEN-P) shaped crystal habits of Form I of FEN were generated using anti-solvent crystallization method. Despite the same polymorphic form and similar particle size distribution, FEN-P demonstrated higher dissolution performance than FEN-R. Crystal face indexation and electrostatic potential (ESP) map provided information on differential relative abundance of various facets and their molecular environment. In FEN-R, the dominant facet (001) is hydrophobic due to the exposure of chlorophenyl moiety. Whereas, in FEN-P the dominant facet (01-1) was hydrophilic due to the presence of chlorine and ester carbonyl groups. Deeper insight on the impact of different facets on dissolution behavior was obtained by energy framework analysis by unveiling strength of intermolecular interactions along various crystallographic facets. Moreover, type 4 apparatus provided higher discriminatory ability over USP Type 2 apparatus, in probing the crystal habit induced differential dissolution performance of FEN. The findings of this study emphasize that crystal habit should be considered as an important critical material attribute (CMA) during formulation development of FEN and due considerations should be given to the selection of the appropriate dissolution testing set-up for establishing in vitro-in vivo correlation.

Keywords: Crystal habit; Density functional theory (DFT); Differential surface anisotropy; Discriminatory dissolution; Fenofibrate; Surface chemistry; USP type 4 apparatus.