Understanding the p-Toluenesulfonamide/Triphenylphosphine Oxide Crystal Chemistry: A New 1:1 Cocrystal and Ternary Phase Diagram

Abstract

A novel 1:1 cocrystal between p-toluenesulfonamide and triphenylphosphine oxide has been prepared and structurally characterized. This 1:1 cocrystal was observed to form during solid state grinding experiments, with subsequent formation of a known 3:2 cocrystal in the presence of excess sulfonamide. Both cocrystals are stable in the solid state. The ternary phase diagram for the two coformers was constructed in two different solvents: acetonitrile and dichloromethane. Examination of these diagrams clarified solution crystallization of both the newly discovered 1:1 cocrystal and the previously reported 3:2 cocrystal, and identified regions of stability for each cocrystal in each solvent. The choice of solvent was found to have a significant effect on the position of the solid state regions within a cocrystal system.

PAT-based design of agrochemical co-crystallization processes: A case-study for the selective crystallization of 1:1 and 3:2 co-crystals of p-toluenesulfonamide/triphenylphosphine oxide

“…Croker et al [13] using small scale experiments. In the current work, the mass fractions of p-TSA/TPPO/MeCN were varied according to the ternary phase diagram shown in Figure 2.…”

“…Small scale batch co-crystallization studies (1 -50 mL) on the p-TSA-TPPO system have previous been reported [6], [13], [29]. The co-crystallization experiments were carried out in a 500 mL jacketed glass vessel fitted with an overhead PTFE pitch blade stirrer.…”

“…The solid and liquid phase characterizations were later compared to samples acquired from each of the batch experimental runs. In house reference samples for the 1:1 and 3:2 p-TSA-TPPO co-crystal forms were prepared according to the procedures of Croker et al [13], [29], solid state characterizations were carried out using the techniques described earlier.…”

“…Co-crystallization can be an effective crystal engineering approach for modifying the crystal structure and properties of an active ingredient [8], [9]. However, many of the current methods used to isolate co-crystal forms such as neat and liquid assisted grinding [10], [11], slurry conversion [12], [13], supercritical fluid enhanced atomization [14], and evaporative co-crystallization [13], [15], [16] cannot be scaled to industrial production capacity. Cooling crystallization is perhaps the most viable route to scale-up, yet there are only a few studies that have explored this method to isolate co-crystals [17]- [19].…”

“…Croker et al [13] isolated and reported the crystal structure of the 1:1 form of p-TSA-TPPO. In their work solid state grinding and small scale evaporative (10 mL) and cooling (50 mL) crystallization methods were applied.…”