Development of amorphous solid dispersion of delamanid, an extremely water-insoluble drug, by hot melt extrusion applying acid-base supersolubilization (ABS) principle.

Delamanid, an antituberculosis drug used for multidrug-resistant tuberculosis, has extremely poor water solubility and a high melting point of ∼195 °C. The current commercial product, Deltyba®, shows incomplete dissolution and food-dependent bioavailability. This study is the first to report the preparation of amorphous solid dispersions (ASD) of delamanid by hot-melt extrusion (HME), made possible by applying the acid-base supersolubilization (ABS) principle using malic acid. Malic acid increased the aqueous solubility of delamanid to 46 mg/mL at pH 1.8, approximately 660 times higher than its amorphous solubility of 70 µg/mL in the fasted state simulated gastric fluid (FaSSGF) at pH 1.6 and ∼60,600 times higher than its amorphous solubility of 0.76 µg/mL in the phosphate-buffered saline (PBS) at pH 6.5. Hot-stage microscopy showed that physical mixtures of delamanid and malic acid (1:8 molar ratio; 1:2 w/w ratio) melted completely at 130 °C, well below the drug's melting point. Determination of complex viscosity using a rheometer confirmed that adding malic acid reduced the viscosity sufficiently for extrusion at 130 °C. Extrudates were characterized by differential scanning calorimetry and powder X-ray diffraction, both of which confirmed complete amorphous conversion for 5% and 10% w/w drug loadings. In vitro dissolution, using an equivalent of 25 mg of delamanid in 250 mL of pH 6.8 buffer at 50 RPM and 37 °C, showed that the formulation containing delamanid, HPMCAS-L, malic acid, and TPGS showed ∼90% drug release at 5% w/w drug loading and >80% at 10% w/w.