The development of an innovative method to improve the dissolution performance of rivaroxaban

Abstract

Recent advancements in the formulation of solid dosage forms involving active ingredient-cyclodextrin complexes have garnered considerable attention in pharmaceutical research. While previous studies predominantly focused on incorporating these complexes into solid states, issues regarding incomplete inclusion prompted the exploration of novel methods. In this study, we aimed to develop an innovative approach to integrate liquid-state drug-cyclodextrin inclusion complexes into solid dosage forms. Our investigation centered on rivaroxaban, a hydrophobic compound practically insoluble in water, included in hydroxypropyl-β-cyclodextrin at a 1:1 M ratio, and maintained in a liquid state. To enhance viscosity, hydroxypropyl-cellulose (2 % w/w) was introduced, and the resulting dispersion was sprayed onto the surface of cellulose pellets (CELLETS®780) using a Caleva Mini Coater. The process parameters were meticulously controlled, with atomization air pressure set at 1.1 atm and a fluidizing airflow maintained at 35-45 m³/h. Characterization of the coated cellets, alongside raw materials, was conducted using Fourier Transform Infrared Spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC) analyses. Physicochemical evaluations affirmed the successful incorporation of rivaroxaban into hydroxypropyl-β-cyclodextrin, with the final cellets demonstrating excellent flowability, compressibility, and adequate hardness. Quantitative analysis via the HPLC-DAD method confirmed a drug loading of 10 mg rivaroxaban/750 mg coated cellets. In vitro dissolution studies were performed in two distinct media: 0.022 M sodium acetate buffer pH 4.5 with 0.2 % sodium dodecyl sulfate (mirroring compendial conditions for 10 mg rivaroxaban tablets), and 0.05 M phosphate buffer pH 6.8 without surfactants, compared to reference capsules and conventional tablet formulations. The experimental capsules exhibited similar release profiles to the commercial product, Xarelto® 10 mg, with enhanced dissolution rates observed within the initial 10 min. This research presents a significant advancement in the development of solid dosage forms incorporating liquid-state drug-cyclodextrin inclusion complexes, offering a promising avenue for improving drug delivery and bioavailability.

Keywords: Dissolution rate; Drug release; Hydroxypropyl-β-cyclodextrin; Inclusion complexes; Rivaroxaban; Solid dosage forms.

Fig. 1

Chemical structures of (a) rivaroxaban and (b) HPβCD.

Fig. 2

FTIR analyses of the samples (I) (a) RIV (inset the characteristic peaks of RIV, 1200-500 cm⁻¹ domain); (b) HPβCD; (c) uncoated cellets; (d) coated cellets; and (II) normalized FTIR analyses for coated and uncoated cellets.

Fig. 3

X-ray diffraction pattern of the samples (a) RIV; (b) HPβCD; (c) uncoated cellets and (d) coated cellets.

Fig. 4

DSC analyses of the samples.

Fig. 5

Enhanced-contrast topographic AFM images, recorded at the scale of (2x2)μm² for: (a) RIV, (b) uncoated cellets, (c) HPβCD, (d) coated cellets; superimposed characteristic line-scans for the pairs of samples: RIV and HPβCD (e) and, respectively uncoated and coated cellets (f).

Fig. 6

The SEM images of (a) cellets powdered with RIV; (b) cellets powdered with RIV and HPβCD; (c) coated cellets; (d) coated cellets in section.

Fig. 7

Images of studies capsules.

Fig. 8

Dissolution profiles in (a) pH 4.5 buffer containing 0.2 % SDS (USP compendial medium) and in (b) pH 6.8 buffer.