We compare two recently developed methods to determine crystal nucleation rates in stirred solutions by using isonicotinamide (INA) in ethanol as an example. The two developed methods make use of the stochastic nature of crystal nucleation, which is reflected in induction time and metastable zone width variations measured in sufficiently small volumes. These methods give easy experimental access to the nucleation rate parameters in solution under industrially realistic crystallization conditions. While the metastable zone width method is less labor intensive, the induction time method has higher accuracy and is easier to analyze.

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We show that, in a controlled and reproducible way, specific solvents lead to specific polymorphic forms of isonicotinamide. We argue on the basis of Raman and FTIR spectroscopy that the hydrogen bonding in solution kinetically drives the nucleation towards a specific form. This generally may lead to good understanding and control of polymorphism and crystal nucleation.The ability to control and predict crystal nucleation is of paramount importance from the viewpoint of crystal engineering, materials synthesis and crystalline product quality. [1][2][3] In this communication we demonstrate the reproducible effect of solvents on the formation of isonicotinamide (INA) polymorphs. We establish that in solvents with strong hydrogen bond acceptors, the dominant configuration of the INA molecules with respect to each other is that of amide-pyridine heterosynthons (headto-tail chains) (Fig. 1). Similarly, solvents with strong hydrogen bond donors lead to dominancy of amide-amide homosynthons (head-to-head dimers). This self-association in solution controls the polymorph nucleation of INA by controlling the building unit attaching to the nucleus.Polymorphism can be defined as the ability of a single chemical compound to form more than one crystal structure. 4 Polymorphism of active pharmaceutical ingredients is the subject of intense interest in both science and industry. 4,5 On the one hand, this is because crystalline product quality aspects such as drug efficacy, bioavailability and safety are affected by the polymorphic form present. On the other hand, polymorphs have economic and intellectual property implications.Often through empirical research, effects of solvent, supersaturation and impurities are observed on polymorph formation. 6 Recently, next to the two known forms of INA, 7 a third form was reported which incidentally and irreproducibly formed during a co-crystal screen from a multicomponent solution. 8 More recently, the difficult to control evaporative crystallization process yielded two new forms of INA.9 Form IV was obtained only as a mixture together with form II and/or V. For form V yields were often poor, typically 10%, and in some cases it could not be obtained.The crystal nucleation of INA is a most interesting process because of the strongly differing packing of form II and the other forms (ESIw). Isonicotinamide form II has been reported to be the most stable form at room temperature. 8 In the structure of form II the amide groups form homosynthons (dimers), 8 which in turn are hydrogen bonded through the oxygen atom and the remaining hydrogen of the amide group. Interestingly, the pyridine group does not participate in hydrogen bonding in the crystal structure of form II, contrary to all other currently known forms of INA. These consist of differently packed head-to-tail chains connected through heterosynthons of the amide and the pyridine group.The classical view of crystal nucleation is that building units attach to and detach from clusters of molecules.10 This attaching building unit could be...

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.