Objectives: Recently, co-amorphous drug-amino acid mixtures were introduced as a promising alternative to other amorphous stabilization approaches such as the use of polymers to form glass solutions. So far, these co-amorphous mixtures have been mainly prepared via vibrational ball milling on a lab scale. In this study, spray-drying was investigated as a scale up preparation method for co-amorphous indomethacin (IND)-amino acid mixtures. In addition, the physico-chemical properties of the different co-amorphous systems were investigated with respect to the amino acids' ability towards co-amorphous salt formation.
Methods: The mixtures were characterized for their solid state properties using differential scanning calorimetry, thermogravimetric analysis and X-ray powder diffraction. Fourier-transform infrared spectroscopy was used to analyze molecular interactions. Furthermore, intrinsic dissolution behaviour, and physical stability at various storage conditions, were examined.
Key findings: Results showed that IND could be converted into an amorphous form in combination with the amino acids arginine (ARG), histidine (HIS) and lysine (LYS) by spray-drying. Solid state characterization revealed elevated glass transition temperatures for all mixtures compared with the pure amorphous drug due to co-amorphization with the amino acids. Furthermore, strong intermolecular interactions in the form of salt/partial salt formation between the drug and amino acids were seen for all blends. All mixtures were physically stable (>10 months) at room temperature and 40°C under dry conditions. Intrinsic dissolution of the co-amorphous mixtures showed an improved dissolution behaviour under intestinal pH conditions for IND-ARG compared with the crystalline and amorphous forms of the drug. On the other hand, IND-LYS and IND-HIS revealed no significant improvement in the intrinsic dissolution rate of IND due to recrystallization of IND during dissolution.
Conclusions: It could be shown that strong intermolecular interactions between drug and co-amorphous coformer that persist during the dissolution are crucial to prevent recrystallization and to enhance dissolution of a co-amorphous formulation.
Keywords: amino acids; co-amorphous; dissolution; salts; spray-drying.
© 2015 Royal Pharmaceutical Society.