Ball-milled valsartan and its combination with mannitol: the case of drug polyamorphism

Valsartan (VAL) is a drug that has low water solubility and low oral bioavailability. Unlike most drugs, bulk VAL has unusual solid-state properties, including the phenomenon of polyamorphism. Furthermore, surprisingly, obtaining the neat VAL in a completely amorphous form does not increase its solubility. In this study, the influence of different ball milling conditions (milling time and speed) on dissolution rate, thermoanalytical and solid-state properties of VAL was studied. The influence of the association of VAL with the hydrophilic carrier mannitol (as physical mixtures and solid dispersions, at different drug/carrier ratios) on drug dissolution, thermoanalytical and solid-state properties was also evaluated. Bulk VAL, milled-VAL and physical mixtures and solid dispersions (SDs) of the drug with mannitol were characterized by differential scanning calorimetry, powder X-ray diffraction analysis and Fourier transformed infrared spectroscopy. Ball milling the neat drug originated self-agglomerated particles, with lower dissolution rate than bulk VAL, and the conversion of VAL from a more ordered amorphous form to another fully amorphous and less soluble form. The same conversion occurred after ball milling of VAL with mannitol (SDs). This change in VAL polyamorphic forms resulting from the ball-milling process had not yet been described in other studies. The highest proportion of mannitol tested (VAL: mannitol 1:3 m/m) promoted a greater increase in the dissolution rate of the drug. A physical mixture prepared in the same composition showed a dissolution profile similar to these SDs. These results demonstrated that the simple association of VAL with mannitol is sufficient to improve its dissolution rate, without changing the solid state of drug.

Automated summary

This study investigates the influence of ball milling conditions and the association of Valsartan (VAL) with mannitol on its dissolution rate and solid-state properties. The results show that ball milling changes the polyamorphic forms of VAL and the association with mannitol improves the dissolution rate of the drug.