Polymorphic Nucleation and Growth Kinetics: Induction-Time Analysis
Understanding the relative nucleation and growth kinetics of polymorphs is essential for controlling crystallization processes and selectively producing desired crystal forms. In the recently published paper, “Nucleation and Growth Kinetics in a Polymorphic System—The Case of Tolfenamic Acid,” the concomitant crystallization of stable Form I and metastable Form II of tolfenamic acid (TFA) from isopropanol was investigated using induction-time distributions obtained from Crystal16 experiments.
🔬 Crystal16 Induction-Time Experiments
A total of 3434 crystallization events were analyzed under different supersaturations, cooling rates, and stirring conditions. Solutions were prepared at approximately 45 °C and cooled to 25 °C at controlled rates of 3–15 °C/min under stirring. Crystal formation was monitored through a decrease in transmissivity, and the induction time was determined from the onset of this decrease. TFA Form I and Form II were identified visually by their white and yellow crystal colors, respectively, with PXRD used to support the phase identification.
📊 Key Results
TFA Form I showed a higher nucleation rate than the metastable Form II under most experimental conditions.
Form II crystallized first in many experiments because its growth time was significantly shorter than that of Form I.
Growth time decreased with increasing supersaturation, indicating faster crystal growth and secondary nucleation at higher supersaturation.
Accounting for polymorph-specific growth times resulted in an approximately 25% reduction in the estimated overall nucleation rate compared with neglecting growth effects.
The developed methodology provides a useful basis for determining nucleation and growth kinetics in polymorphic systems and can support the construction of kinetic phase diagrams, with potential applications in pharmaceutical crystallization and process design.
👏We congratulate and thank the authors for their valuable contributions and insights.
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