# Spray-Dried Inclusion Complex of Apixaban with β-Cyclodextrin Derivatives: Characterization, Solubility, and Molecular Interaction Analysis

## TL;DR

This study improves the solubility of apixaban, an anticoagulant, using spray-dried inclusion complexes with β-cyclodextrin derivatives.

## Contribution

DM-β-CD-based inclusion complexes significantly enhance apixaban solubility and stability.

## Key findings

- DM-β-CD formed the most stable inclusion complex with apixaban (Kc = 371.92 M−1).
- DM-ICs achieved up to a 78.7-fold solubility increase in water compared to pure apixaban.
- Molecular docking confirmed stable inclusion with the lowest binding free energy (−8.01 kcal/mol).

## Abstract

Apixaban (APX) is a direct oral anticoagulant with low aqueous solubility and limited bioavailability. This study aimed to improve APX solubility by forming spray-dried inclusion complexes (ICs) with β-cyclodextrin (β-CD) derivatives. ICs were prepared using hydroxypropyl-β-CD (HP-β-CD), sulfobutylether-β-CD (SBE-β-CD), randomly methylated-β-CD (RM-β-CD), and heptakis(2,6-di-O-methyl)-β-CD (DM-β-CD). Complex formation (1:1 stoichiometry) was confirmed by phase solubility studies and Job’s plots. The ICs were characterized by SEM, PXRD, DSC, and FTIR, and their saturated solubility was evaluated. Molecular docking assessed host–guest interactions. Among the tested carriers, DM-β-CD exhibited the highest stability constant (KC = 371.92 M−1) and produced amorphous ICs. DM-ICs achieved the greatest solubility enhancement at all pH conditions, with a maximum solubility of 1968.7 μg/mL at pH 1.2 and ~78.7-fold increase in water compared with pure APX. Docking results supported stable inclusion with the lowest binding free energy (−8.01 kcal/mol). These findings indicate that DM-β-CD-based ICs effectively enhance APX dissolution and show potential as solubilizing carriers for oral dosage forms.