Nucleation, crystal growth, nuclei stability, and polymorph selection in supercooled tolbutamide melt.

Nucleation is an essential step of overall crystallization, yet crystal nuclei are elusive to direct observation due to their small size and transient nature. A method for assessing the nuclei size distribution and growth rate based on selective melting/dissolving was developed recently, making use of the rapid heating/cooling rate available in fast scanning calorimetry. The method was first employed to study the nuclei in the polymer poly-L-lactic acid. Here we investigate the crystal nuclei of tolbutamide, a molecular compound. We show that while the general behavior of tolbutamide is compatible with the classic nucleation theory (CNT) and is in agreement with previous results for poly-L-lactic acid, there are some peculiarities. First, tolbutamide nuclei display extreme thermal stability, surviving heating above the melting onset of the polymorph forming at the same conditions. Second, the nuclei size distribution shows a sharp cut-off at the high end of the distribution. Finally, the difference in the growth rate of nuclei and crystals of tolbutamide is even higher (about 5 orders of magnitude) than what was determined for poly-L-lactic acid previously.