Thermodynamic Polymorph Selection in Enantiotropic Systems Using Supersaturation-Controlled Batch and Semibatch Cooling Crystallization

Supersaturation control (SSC) is a simple yet effective technique to control, among other properties, the purity, shape, and polymorphic form of crystals during the crystallization process. However, for the enantiotropic polymorph systems it is difficult to efficiently operate the traditional batch SSC because of the intersecting solubility lines and hence the temperature dependence of polymorph stability. From a thermodynamic perspective, the transition temperature in a batch crystallization is the minimum final temperature for the polymorph that is stable at high temperature, and it is the maximum initial temperature for the polymorph that is stable at lower temperatures. The existence of a transition point between the two polymorphs often makes it difficult to produce consistently one or the other form with good yield in a batch crystallization process. Due to the constant-temperature operation, continuous tank crystallizers could overcome this problem, but the scale of production and other technology challenges often does not justify their application. This paper proposes a semibatch cooling SSC strategy, having as the manipulated variable the feed flow rate of a high-temperature, concentrated inlet stream in the same solvent system as used in the crystallization process. The crystallizer temperature is fixed under the transition temperature, and the concentration corresponding to the supersaturation set point is undersaturated for the counter polymorph, ensuring in this way thermodynamic polymorph selection. The system is presented through the case study of p-aminobenzoic acid (PABA) crystallization from ethanol for SSC of both enantiotropic polymorphs: alpha-PABA can be obtained in both batch and semibatch operation. According to the literature, beta-PABA cannot be easily obtained in batch cooling crystallization, but the semibatch setup was able to produce it consistently without yield limitations due to the transition temperature.