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.

The effect of the triblock co-polymer, Pluronic P123 (PP123) on the growth of succinic acid crystals from aqueous solutions is reported at two batch process scales: 10 mL and 350 mL. The presence of small quantities of PP123 is shown to modify the crystal morphology from plate-like crystals to block-like crystals, in a fully reproducible manner. Increasing the quantity of polymer present, or the concentration of succinic acid used, produces needle-like crystals that are less favorable for processing. In-line process analytical tools (FBRM, PVM and Raman) were implemented for the larger volume batch processes, allowing the crystallization to be monitored in real-time. The effect of the polymer on the metastable zone width (MSZW) has also been determined in designing the crystallization experiments and is presented. In addition, the effect of the individual blocks of the co-polymer, poly(ethylene glycol) and poly(propylene glycol) on the crystal morphology was examined and these findings, together with face indexing and knowledge of the underlying crystal structure, have allowed a possible mechanism to be constructed for the interaction of the polymer with the crystal surface. This mechanism is supported by subsequent re-crystallization experiments following washing of the block-like crystals with a non-polar solvent.

Purity is a critical quality attribute for both pharmaceutical and biopharmaceutical products. The presence of impurities (solvents, salts, or byproducts of the synthetic path) in drugs can cause a reduction of their effectiveness or can even be toxic for the patients. Biopharmaceuticals are produced by biological processes which are difficult to control. Therefore, the amount of impurities that has to be removed can be significantly higher than in the case of synthetic pharmaceuticals. The aim of this work is to exploit process analytical technology tools and different feedback control strategies (T-control, direct nucleation control, and supersaturation control) for the crystallization of a biopharmaceutical product. UV/vis spectroscopy and focused beam reflectance measurement combined with a Crystallization Process Informatics System (CryPRINS) were used to improve the crystal size distribution and purity of crystallized vitamin B12. The different feedback control strategies were compared to classical crystallization techniques in terms of purity of the final crystal and quality of the crystal size distribution, and it is shown that using suitable crystallization feedback control strategies, the purity and quality of crystals can be improved.

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