Polymorphism Control through a Single Nucleation Event

Recently, we identified that the single nucleus mechanism, in which all crystals in the suspension originate from the same parent single crystal, might occur more generally than is currently recognized, even in larger volumes. This has important implications for the control of industrial crystallization processes of polymorphic compounds. In this paper, we used polymorphism as a tool to validate this single nucleus mechanism. Isonicotinamide (INA) crystallizes as form II in ethanol solutions, form I in nitromethane, and form IV in nitrobenzene solutions. The metastable form I and form IV, furthermore, only very slowly transform to the stable form II in solvent mixtures of ethanol-nitromethane and ethanol-nitrobenzene. We performed multiple crystallization experiments in solvent mixtures of ethanol-nitromethane and ethanol-nitrobenzene which all resulted in the formation of either pure form I or pure form II and either pure form II or pure form IV, respectively. In ethyl acetate, 4-hydroxyacetophenone (4HAP) crystallizes as form II at lower concentrations and as form I at higher concentrations. Crystallization of 4HAP as a function of concentration on a 3 mL scale results in either pure form I or pure form II. This can be well explained by the single nucleus mechanism. In terms of polymorphism, the control can be achieved by controlling the primary nucleation event that leads to the single crystal, which in turn defines the crystal form of the secondary nuclei. Seeding approaches using only a single crystal would then lead to the avoidance of primary nucleation and thus control over the polymorph obtained.