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  • Title: Co-former selection for co-amorphous drug-amino acid formulations.
    Author: Kasten G, Löbmann K, Grohganz H, Rades T.
    Journal: Int J Pharm; 2019 Feb 25; 557():366-373. PubMed ID: 30578980.
    Abstract:
    We have previously developed a fast screening method on the ability of twenty amino acids (AA) to form co-amorphous formulations with six drugs upon ball milling. In this work, the potential advantages in physical stability and dissolution rate of the 36 successful co-amorphous formulations, compared to the pure amorphous drug, were further investigated. The physical stability of the formulations at dry conditions was assessed by X-ray powder diffraction (XRPD) and their thermal behavior by differential scanning calorimetry (DSC). In addition, the intrinsic dissolution rate (IDR) of all formulations was determined in phosphate buffer (10 mM, pH 6.8). Finally, all the co-amorphous formulations were summarized into different groups, according to the outcome of the co-formability, physical stability and dissolution rate screenings, and guidelines could be drawn for selection of co-formers for a new given drug: (i) For acidic drugs, basic AAs (arginine, histidine, and lysine) are good co-formers with respect to the three critical quality attributes: co-formability, physical stability and dissolution. High glass transition temperatures (Tg), physical stability for 1-2 years, and accelerated IDR were observed. (ii) For basic and neutral drugs, non-polar AAs with aromatic groups such as tryptophan (TRP) and phenylalanine (PHE) should be explored as first choice. These combinations presented high Tgs, which generally translated into good physical stability. The IDR of TRP- and PHE-based formulations were usually superior to the IDR of the pure amorphous drugs; (iii) Non-polar AAs with aliphatic structures such as leucine, isoleucine, methionine and valine did not provide an increase in Tg or IDR compared to the pure amorphous drug, and appear to be less feasible AAs for co-amorphous formulations.
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