Abstract
Ball-milling is usually used to prepare co-amorphous drug–amino acid (AA) mixtures. In this study, co-amorphous drug–AA mixtures were produced using spray-drying, a scalable industrially preferred preparation method. The influence of the solvent type and solvent composition was investigated. Mixtures of indomethacin (IND) and each of the three AAs arginine, histidine, and lysine were ball-milled and spray-dried at a 1:1 molar ratio, respectively. Spray-drying was performed at different solvent ratios in (a) ethanol and water mixtures and (b) acetone and water mixtures. Different ratios of these solvents were chosen to study the effect of solvent mixtures on co-amorphous formulation. Residual crystallinity, thermal properties, salt/partial salt formation, and powder dissolution profiles of the IND–AA mixtures were investigated and compared to pure crystalline and amorphous IND. It was found that using spray-drying as a preparation method, all IND–AA mixtures could be successfully converted into the respective co-amorphous forms, irrespective of the type of solvent used, but depending on the solvent mixture ratios. Both ball-milled and spray-dried co-amorphous samples showed an enhanced dissolution rate and maintained supersaturation compared to the crystalline and amorphous IND itself. The spray-dried samples resulting in co-amorphous samples were stable for at least seven months of storage.
Highlights
Oral pharmaceutical products comprise about 70% of all pharmaceutical products, making oral administration the most convenient and preferred route of drug delivery [1,2]
IND–amino acid (AA) mixtures (IND–ARG, IND–HIS, and IND–LYS) at a 1:1 molar ratio were investigated for their ability to form co-amorphous systems using both BM and SD, where the emerging technique of SD was compared to the established technique of BM
This study shows that, in contrast to ball-milling, IND mixtures could be successfully converted into co-amorphous forms by spray-drying with the three amino acids used
Summary
Oral pharmaceutical products comprise about 70% of all pharmaceutical products, making oral administration the most convenient and preferred route of drug delivery [1,2]. A major challenge with the use of amorphous drugs is their low physical stability, that is, their tendency to recrystallize upon formulation, storage, or administration [6]. This has led to an urgent need to increase the understanding of the link between the physicochemical properties of an amorphous drug and potential interactions with common excipients on the overall physical stability of amorphous forms. AAs are especially promising excipients as they can form strong molecular interactions with drugs, which may play a crucial role in stabilizing co-amorphous formulations and increasing drug dissolution rates [9,10,11]
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