Modifiers regulate crystal morphology by generating lattice defects

Crystal morphology plays a pivotal role in all applications because it affects the performance and processing behaviors of crystals. Foreign compounds are often employed to control the crystal morphology; conversely, morphology variations are sometimes attributed to uncontrolled impurities present in the crystallizing solution. Here, we explore the impact of modifiers on the crystallization and morphology of mefenamic acid (MFA), a nonsteroidal anti-inflammatory drug. We focus on the roles of benzoic acid, 2-chlorobenzoic acid, and 2,3-dimethylaniline, compounds that may be retained as minor components after MFA synthesis. We explored the effects of these compounds at varying MFA supersaturation levels. Whereas the additives did not alter the polymorphic form of MFA, they significantly modified crystal morphology, leading to elongated and blade-like crystals. In contrast to numerous published cases, these compounds do not affect the growth rates of the dominant crystal faces. Instead, we show that the observed morphology changes are due to modifier-driven crystal twinning that may be initiated by disruptions of the crystal nucleation. These findings highlight the importance of considering nonclassical nucleation , wherein impurities and modifiers may influence crystallization through pathways beyond direct surface adsorption such as cluster formation and lattice disruption. This study provides critical insights into the role of foreign compounds in crystal engineering, emphasizing the need for an integrated outlook on their effects on crystal nucleation and growth to optimize crystallization strategies and enhance drug performance.