A computational-based approach to fabricate Ceritinib co-amorphous system using a novel co-former Rutin for...

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Computational Chemistry

Background:

• Ceritinib (CRT) exhibits poor solubility and bioavailability, limiting its therapeutic efficacy.
• Co-amorphous materials (CAMs) offer a promising strategy to enhance the physicochemical properties of poorly soluble drugs.
• Molecular simulations can predict and guide the design of effective co-amorphous systems.

Purpose of the Study:

• To design novel Ceritinib-Rutin co-amorphous materials (CAMs) with improved solubility and bioavailability.
• To utilize computational modeling for co-former selection and interaction prediction.
• To characterize the solid-state properties, stability, and pharmacokinetic performance of the developed CAMs.

Main Methods:

• Molecular simulations were employed to estimate binding energy and intermolecular interactions for co-former selection.
• Ceritinib-Rutin co-amorphous materials (CAMs) were prepared using the solvent evaporation method.
• Solid-state characterization involved DSC, XRPD, and FT-IR; physical stability was assessed under accelerated conditions.
• Solubility, dissolution, permeability (everted gut sac method), and pharmacokinetic parameters (AUC 0-t, Cmax) were evaluated.

Main Results:

• Molecular simulations identified Rutin (RTH) as a suitable co-former for Ceritinib (CRT).
• Characterization confirmed the formation of a single amorphous phase with intermolecular interactions between CRT and RTH.
• Co-amorphous materials exhibited excellent physical stability for up to 4 months and maintained supersaturation for 24 hours.
• CRT:RTH CAMs demonstrated a 2-fold increase in permeability and significant improvements in solubility, dissolution, and pharmacokinetic exposure (3.1-fold AUC, 2-fold Cmax).

Conclusions:

• Ceritinib-Rutin co-amorphous materials (CAMs) were successfully designed using molecular simulations and solvent evaporation.
• The developed CAMs exhibit enhanced solubility, dissolution, permeability, and bioavailability compared to physical mixtures.
• This study highlights the potential of computational modeling and co-amorphous technology for improving the delivery of poorly soluble drugs like Ceritinib.