Enhancing the Drug Release and Physicochemical Properties of Rivaroxaban via Cyclodextrin Complexation: A Comprehensive Analytical Approach

Abstract

Background/Objectives: Rivaroxaban, an oral anticoagulant, shows poor aqueous solubility, posing significant challenges to its bioavailability and therapeutic efficiency. The present study investigates the improvement of rivaroxaban's solubility through the formation of different inclusion complexes with three cyclodextrin derivatives, such as β-cyclodextrin (β-CD), methyl-β-cyclodextrin (Me-β-CD), and hydroxypropyl-β-cyclodextrin (HP-β-CD) prepared by lyophilization in order to stabilize the complexes and improve dissolution characteristics of rivaroxaban. Methods: The physicochemical properties of the individual compounds and the three lyophilized complexes were analysed using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). Results: FTIR spectra confirmed the formation of non-covalent interactions between rivaroxaban and the cyclodextrins, suggesting successful encapsulation into cyclodextrin cavity. SEM images revealed a significant morphological transformation from the crystalline structure of pure rivaroxaban and cyclodextrins morphologies to a more porous and amorphous matrix in all lyophilized complexes. XRD patterns indicated a noticeable reduction in drug crystallinity, supporting enhanced potential of the drug solubility. TGA analysis demonstrated improved thermal stability in the inclusion complexes compared to the individual drug and cyclodextrins. Pharmacotechnical evaluation revealed that the obtained formulations (by comparison with physical mixtures formulations) possessed favorable bulk and tapped density values, suitable compressibility index, and good flow properties, making all suitable for direct compression into solid dosage forms. Conclusions: The improved cyclodextrins formulation characteristics, combined with enhanced dissolution profiles of rivaroxaban comparable to commercial Xarelto^® 10 mg, highlight the potential of both cyclodextrin inclusion and lyophilization technique as synergistic strategies for enhancing the solubility and drug release of rivaroxaban.

Keywords: drug release; hydroxypropyl-β-cyclodextrin; methyl-β-cyclodextrin; pharmaceutical formulation; rivaroxaban; solubility enhancement; β-cyclodextrin.

Figure 1

The phase-solubility diagram of rivaroxaban–β-CD, rivaroxaban–Me-β-CD, and rivaroxaban–HP-β-CD systems.

Figure 2

FTIR spectra of (a) rivaroxaban, (b) β-cyclodextrin, (c) methyl-β-cyclodextrin, (d) hydroxypropyl-β-cyclodextrin, (e) inclusion complex of rivaroxaban-β-cyclodextrin, (f) inclusion complex of rivaroxaban-methyl-β-cyclodextrin, and (g) inclusion complex of rivaroxaban-hydroxypropyl-β-cyclodextrin.

Figure 3

XRD diffraction spectra of (a) rivaroxaban, β-cyclodextrin, and rivaroxaban-β-cyclodextrin; (b) rivaroxaban, methyl-β-cyclodextrin, and rivaroxaban-methyl-β-cyclodextrin; (c) rivaroxaban, hydroxypropyl-β-cyclodextrin, and rivaroxaban-hydroxypropyl-β-cyclodextrin.

Figure 4

SEM images of (a) rivaroxaban, (b) β-cyclodextrin, (c) methyl-β-cyclodextrin, (d) hydroxypropyl-β-cyclodextrin, (e) inclusion complex of rivaroxaban-β-cyclodextrin, (f) inclusion complex of rivaroxaban-methyl-β-cyclodextrin, and (g) inclusion complex of rivaroxaban-hydroxypropyl-β-cyclodextrin.

Figure 5

Thermal curves of (a) rivaroxaban, (b) β-cyclodextrin, (c) methyl-β-cyclodextrin, (d) hydroxypropyl-β-cyclodextrin, (e) inclusion complex of rivaroxaban-β-cyclodextrin, (f) inclusion complex of rivaroxaban-methyl-β-cyclodextrin, and (g) inclusion complex of rivaroxaban-hydroxypropyl-β-cyclodextrin.

Figure 6

Granulometric analysis of binary systems and mixtures for direct compression.

Figure 7

Tablets appearance. F1–F6 represent the code for the pharmaceutical formulations.

Figure 8

In vitro dissolution profiles of rivaroxaban from test formulations (F1–F6) compared with the reference product (Xarelto^® 10 mg) in (a) pH 4.5 sodium acetate buffer with 0.2% SDS and (b) pH 6.8 phosphate buffer. Results are presented as mean ± SD (n = 3).