Crystallization of Metastable Isonicotinamide Polymorphs and Prevention of Concomitant Crystallization by Additives

Concomitant crystallization of polymorphs is a major problem for the pharmaceutical industry, and in general, a better understanding of this phenomenon is necessary to ensure the crystallization of just one desired polymorph. Isonicotinamide (INA) forms six polymorphs which often crystallize concomitantly. Here, we studied whether the use of crystallization additives can facilitate the formation of INA metastable forms and prevent concomitant crystallization. Crystallization of INA was explored under different conditions by performing cooling and evaporative crystallization from different pure solvents and in the presence of crystallization additives. Some additives, such as naphthalene-1,5-diol, 4-carboxybenzeneboronic acid, and 2-picolinic acid, provided achieving crystallization control. Theoretical calculations allowed us to gain partial insight into the factors responsible for the polymorphic outcome of INA crystallization. The crystal structures of INA polymorphs II, IV, and VI, which often crystallize concomitantly, are almost identical. Therefore, it is possible that the energy barriers of nucleation and crystal growth rates for these polymorphs are highly similar, whereas, in the presence of additives, the crystallization of structurally more different Forms III or I could be achieved by altering these energy barriers.