Dissolution performance of binary amorphous drug combinations—Impact of a second drug on the maximum achievable supersaturation

Abstract

An increased number of amorphous formulations of poorly water soluble drugs are being introduced into the market due to their higher transient solubility and thus faster absorption and higher bioavailability. While most amorphous drug products contain a single drug substance, there is a growing trend towards co-formulating compounds in the same dosage form to improve patient compliance. The purpose of the present work was to evaluate the dissolution behavior and maximum achievable solution concentrations of amorphous solid dispersions of co-formulated ritonavir and lopinavir, and to compare the results with individual amorphous solid dispersion formulations. Dispersions of ritonavir and lopinavir were prepared in polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose acetate succinate (HPMCAS) at a 20% (w/w) total drug loading, both alone and in combination, at three different lopinavir:ritonavir weight ratios. Amorphous films containing both drugs, but no polymer, were also prepared. The dissolution behavior of the dispersions and the amorphous films in non-sink conditions was evaluated, using ultracentrifugation to separate any colloidal material from molecularly dissolved drug. Nanoparticle tracking analysis was used to characterize colloidal material formed during the dissolution process. Results from the dissolution study revealed that, although supersaturated solutions resulted following dissolution, the maximum achievable concentration of each drug, when present in combination, was dramatically lower than when the individual dispersions were dissolved. The maximum achievable solution concentration for systems containing both drugs was found to decrease as the mole fraction of the drug in the amorphous phase decreased. The type of polymer used to formulate the dispersion also appeared to influence the dissolution behavior whereby the HPMCAS dispersions dissolved rapidly, resulting in the generation of a nanodroplets, while the PVP dispersions did not produce as many colloidal species. These results highlight the need to consider potential decreases in achievable supersaturation for formulations containing more than one amorphous compound.