Kinetic Difference between Concomitant Polymorphism and Solvent-mediated Phase Transformation: A Case of Tolfenamic Acid

Detection of two or multiple polymorphs in solution is a result of concomitant polymorphism or due to solvent-mediated phase transition. In this work, crystallization of tolfenamic acid (TFA) was conducted under several different supersaturation and temperature conditions. Form I and form II were identified from crystallized samples. Solute concentration and polymorph composition were respectively determined by UV-vis and Raman spectroscopy through the course of crystallization. Kinetic modeling was also conducted to further examine the crystallization kinetics, revealing that the observed simultaneous nucleation of the two forms is characteristically associated with an intermediate recession of the relative amount of form I in crystal mixtures. This unambiguous kinetic event proves to be indicative of the concomitant crystallization of TFA, shedding light on its nucleation mechanism.