Development of a screening method for co-amorphous formulations of drugs and amino acids

Abstract

Using amino acids (AA) as low molecular weight excipients in the preparation of co-amorphous blends with the aim to stabilize the drug in the amorphous form have been discussed in a range of studies. However, there is currently no theoretical consensus behind which AA would be a suitable co-former for a given drug. In this work, a fast screening process to assess the co-former feasibility in co-amorphous drug-AA blends has been developed on the basis of the amorphization kinetics upon oscillatory ball milling. For this purpose, six model drugs were combined with 20 different AAs and co-milled at an equimolar ratio for different times (1, 5, 15, 30 and 60min). The degree of amorphization was then studied for the different time points by determination of the area under the curve of the diffraction peaks in X-ray powder diffraction measurements. The results of this study suggest that the choice of AA as co-formers for the formation of the co-amorphous blend could be significantly inferred after 15min of milling, since a crystallinity decrease higher than 90% after 15min resulted in successful co-amorphization in approximately 90% of the mixtures after 60min of milling. The results furthermore suggested that non-polar AAs, such as tryptophan, phenylalanine, leucine, isoleucine, methionine, valine and proline, are a good first choice in the selection of a co-former for a given drug in a co-amorphous formulation. Basic AAs appear suitable for amorphous salt formation in the case of acidic drugs. Acidic AAs however, were shown to be generally poor co-formers for co-amorphous systems.