Active Polymorphic Feedback Control of Crystallization Processes Using a Combined Raman and ATR-UV/Vis Spectroscopy Approach

The nucleation of the metastable form of a substance or of a mixture of more forms is very common in polymorphic crystallization. Additionally, in industry seed may contain a variable amount of metastable polymorph as impurity, resulting from previous batches or milling, which may compromise the desired outcome of obtaining product of the stable polymorphic form. The natural polymorphic conversion into the stable form is often too slow compared to the normal batch times. In this work, a control strategy to quickly obtain crystals of pure stable form was developed. An active polymorphic feedback control (APFC) strategy is proposed, based on the use of a combination of Raman and ATR-UV/vis spectroscopy using a hierarchical control implementation. The approach detects the formation of the polymorphic mixture and eliminates the metastable form by triggering a controlled dissolution cycle and allowing the growth of the stable form using supersaturation control. A calibration-based approach is used for the solute concentration measurement for the supersaturation control, while for the Raman measurement a calibration-free technique is applied based on the identification of a specific peak in the spectrum associated with the presence of the metastable form. The approach is evaluated in the case of the cooling crystallization of ortho-aminobenzoic acid, used as a model system. It is shown that the proposed APFC technique can lead to pure polymorphic forms in the case of an unseeded crystallization process where nucleation of polymorph mixtures occurs or for seeded crystallization with contaminated seed with unwanted polymorph impurity.