Crystal Engineering as an Efficient Medicinal Chemistry Tool for Animal PK Bioavailability Enhancement in Early...

Background: A lean crystal engineering study was performed on the early pre-clinical POLθ inhibitor MSC178 to enable sufficient exposure for high-dose PK studies. Methods: COSMOquick-derived excess enthalpies in combination with a toxicological assessment of co-formers were used for the selection of four co-formers. Experimental crystallization trials were performed in a staged approach from a 15 mg scale, over a 50 mg upscale, to a final g-scale upscale of the most promising co-crystal form with 2,4-DHBA. Results: The 2,4-DHBA co-crystal form revealed more enhanced and sustained supersaturation plateaus in FaSSIF compared to the amorphous free base form, the 3,4-DHBA co-crystal form, and the 1,2-EDSA salt form. Moreover, the 2,4-DHBA co-crystal form was shown to be physically stable in the suspension vehicle for the PK study. The high physical stability toward physical-form conversion in the suspension vehicle as well as the more sustained supersaturation plateau in the non-sink dissolution profile could be attributed to the intrinsic features of the crystal structure as well as the assessed surface hydrophilicity of the co-crystal particles, both suggesting that rather hydrophobic surfaces are present that help preferentially attract stabilizing surfactants from the dissolution medium (taurocholate) and from the suspension vehicle (polysorbate, methocel), respectively. Successful upscale of the 2,4-DHBA co-crystal form was achieved in the small g-scale, revealing mainly isotropic crystal growth in primary particles as well as a pronounced tendency toward isotropically shaped dendrite-like secondary particles, both favored by a multi-dimensional hydrogen bonding network being present. Excellent agreement was shown for the extent of in vitro supersaturation behavior and in vivo exposure gain in the high-dose PK study for the 2,4-DHBA co-crystal form versus the amorphous free form. Conclusions: The co-crystal strategy can be successfully developed in early pre-clinical industrial research with lean methodologies to optimize sub-optimal phys.-chem. properties of a free base compound to achieve improved and less variable in vivo exposure between animals in high-dose PK studies.