A novel drug-drug coamorphous system without molecular interactions: improve the physicochemical properties of tadalafil and repaglinide

Abstract

Tadalafil and repaglinide, categorized as BCS class II drugs, have low oral bioavailabilities due to their poorly aqueous solubilities and dissolutions. The aim of this study was to enhance the dissolution of tadalafil and repaglinide by co-amorphization technology and evaluate the storage and compression stability of such coamorphous system. Based on Flory-Huggins interaction parameter (χ ≤ 0) and Hansen solubility parameter (δ _t ≤ 7 MPa^0.5) calculations, tadalafil and repaglinide was predicted to be well miscible with each other. Coamorphous tadalafil-repaglinide (molar ratio, 1 : 1) was prepared by solvent-evaporation method and characterized with respect to its thermal properties, possible molecular interactions. A single T _g (73.1 °C) observed in DSC and disappearance of crystallinity in PXRD indicated the formation of coamorphous system. Principal component analysis of FTIR in combination with Raman spectroscopy and Ss ¹³C NMR suggested the absence of intermolecular interactions in coamorphous tadalafil-repaglinide. In comparison to pure crystalline forms and their physical mixtures, both drugs in coamorphous system exhibited significant increases in intrinsic dissolution rate (1.5-3-fold) and could maintain supersaturated level for at least 4 hours in non-sink dissolution. In addition, the coamorphous tadalafil-repaglinide showed improved stability compared to the pure amorphous forms under long-term stability and accelerated storage conditions as well as under high compressing pressure. In conclusion, this study showed that co-amorphization technique is a promising approach for improving the dissolution rate of poorly water-soluble drugs and for stabilizing amorphous drugs.

Fig. 1. Molecular structures of tadalafil (a) and repaglinide (b).

Fig. 2. PXRD patterns of crystalline tadalafil (a), crystalline repaglinide (b), physical mixture (1 : 1) (c), amorphous tadalafil (d), amorphous repaglinide (e), and coamorphous system (f).

Fig. 3. (A) DSC thermograms for crystalline tadalafil (a), crystalline repaglinide (b), physical mixture (1 : 1) (c), amorphous tadalafil (d), amorphous repaglinide (e) and coamorphous system (f) determined at 10 °C min⁻¹, (B) DSC thermogram for a 1 : 1 physical mixture of tadalafil and repaglinide determined at 2 °C min⁻¹.

Fig. 4. FTIR spectra of crystalline tadalafil (a), crystalline repaglinide (b), physical mixture (1 : 1) (c), amorphous tadalafil (d), amorphous repaglinide (e), amorphous physical mixture (1 : 1) (f) and coamorphous system (g).

Fig. 5. Score plot of crystalline tadalafil and REP, amorphous tadalafil and repaglinide, physical mixture, amorphous physical mixture and coamorphous tadalafil–repaglinide from PCA analysis of their FTIR spectra.

Fig. 6. Raman spectra of crystalline tadalafil (a), crystalline repaglinide (b), physical mixture (1 : 1) (c), amorphous tadalafil (d), amorphous repaglinide (e), amorphous physical mixture (1 : 1) (f) and coamorphous system (g).

Fig. 7. Ss ¹³C NMR spectra of crystalline tadalafil (a), crystalline repaglinide (b), physical mixture (1 : 1) (c), amorphous tadalafil (d), amorphous repaglinide (e), amorphous physical mixture (1 : 1) (f) and coamorphous system (g).

Fig. 8. Equilibrium solubility of (A) tadalafil from crystalline tadalafil, physical mixture and coamorphous system and (B) repaglinide from crystalline repaglinide, amorphous repaglinide, physical mixture and coamorphous system in four aqueous media (n = 3, x ± s).

Fig. 9. Intrinsic dissolution profiles of (A) tadalafil in crystalline tadalafil (), physical mixture () and coamorphous system () and (B) repaglinide in crystalline repaglinide (), physical mixture () and coamorphous system () in water (n = 3, x ± s).

Fig. 10. Supersaturation dissolution profiles of (a) tadalafil in crystalline tadalafil (), physical mixture () and coamorphous system () and (b) repaglinide in crystalline repaglinide (), physical mixture () and coamorphous system () in water (A) and pH 6.8 phosphate buffer (B) (n = 6, x ± s).

Fig. 11. PXRD patterns for amorphous tadalafil (a), amorphous repaglinide (b) and coamorphous system (c) stored at 25 °C/60% RH and 40 °C/75% RH over a specified period.

Fig. 12. DSC patterns for coamorphous system under different pressure, and stored at 25 °C/60% RH and 40 °C/75% RH over a specified period.

Fig. 13. Photomicrographs of surface-scraped species of amorphous tadalafil tablet (A), amorphous repaglinide tablet (B) and coamorphous tablet (C) under different pressure conditions.