Co-Former Selection for Coamorphous Amino Acid/Spironolactone Formulations and Exploration of the Amorphization Kinetics of Systems
Maolin Li, Zhang Jin, Dandan Han, Songgu Wu, Junbo Gong
Abstract
Spironolactone (SPL) has low bioavailability due to its poor solubility. Preparing amino acid (AA)/SPL coamorphous systems is one of the effective ways to overcome this disadvantage. In this study, mixtures of SPL and 10 different AAs were prepared by the ball milling method. Solid-state characterization revealed that only l -phenylalanine (PHE) and l -tryptophan (TRP) could successfully form a homogeneous coamorphous system with SPL. In addition, we investigated the formation of AA/spironolactone (SPL) coamorphous systems and successfully defined two reliable parameter indicators of formation: the difference in octanol–water partition coefficient (Δ log P ) < 4.5 and a negative mixing enthalpy (Δ H mix ) value. The results of the amorphization kinetics showed that the AAs with low lattice energy amorphized first, whereas the SPL (201) crystal plane, possessing the highest crystal face energy of 1.89 × 10 –5 kcal/m 2, disappeared at last in the process of ball milling. Stability experimental data showed that the TRP/SPL coamorphous system possesses better physical stability than the PHE/SPL coamorphous system, which was due to the higher hydrogen bond binding energy (−11.67 kcal/mol) of the TRP/SPL coamorphous system. Finally, powder dissolution experiments of the coamorphous systems indicated that the TRP/SPL coamorphous system exhibited a threefold improvement in dissolution rate compared to pure crystalline drug SPL.