Drug Substance and Former Structure Property Relationships in 15 Diverse Pharmaceutical Co-Crystals

The pharmaceutical co-crystal approach can be used to modify physicochemical properties of new chemical entities. However, methodical studies of how co-crystal former selection influences properties of the resulting co-crystal, such as melting point and solubility, are needed. Consequently, we investigated 15 co-crystals of AMG 517 and three related molecules using di-and triacids as well as amides as co-crystal formers. Fourteen co-crystals and one partial salt were prepared as judged by pK(a) values and single crystal data. In addition, we found that our ability to form co-crystals was significantly influenced by even minor changes to the chemical structure of the drug substance. Furthermore, we discovered that all AMG 517 co-crystals, which we obtained single crystal structure for, utilize the same hydrogen bond donor (amide) and acceptor (benzothiazole) on the drug substance. Additional hydrogen bonds were observed in all of the co-crystals. In this study, we found little correlation between the melting point of the co-crystal former and the co-crystal, and no correlation between the melting point and solubility of the co-crystals, although some correlations within specific classes were found. Therefore, as the diversity of co-crystal formers increases, rational design of AMG 517 co-crystals becomes more difficult, and obtaining the desired physicochemical properties would still have to involve experimental testing.