Careful Navigation of the Crystallographic Landscape of MK-8970: A Racemic Acetal Carbonate Prodrug of Raltegravir

MK-8970 is an acetal carbonate prodrug of raltegravir (Isentress). This work presents the Merck team’s investigations into the polymorphism of MK-8970, the thermodynamic relationship between the discovered crystalline forms, and implementation of that knowledge toward solving key processing challenges. MK-8970 was found to exist in two enantiotropic polymorphs, with a crossover temperature of approximately 117 °C, as determined from solubility data. Form 2 of MK-8970, the stable form at ambient temperature, was confirmed to be a true racemic crystal form and not a conglomerate on the basis of single-crystal X-ray structure data. In preparation for scale-up of MK-8970, form control was established by mapping out solubility curves for the relevant crystalline forms in ethyl acetate as a function of temperature. Lastly an investigation of the relative solubilities of MK-8970 and a troublesome imidate impurity identified improved solvent systems for maximizing rejection of this impurity while avoiding significant yield losses