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The relative stabilities of the two anhydrous polymorphs and the monohydrate of piroxicam in ethanol/water mixtures and the crystallization behavior of the solid forms in the presence of 11 additives were studied. At 37°C, form II is thermodynamically more stable than form I, while the relative stability of form II and the monohydrate depends on the water concentration in the solution. The total Hansen solubility parameter d T and the hydrogen bonding solubility parameter d H of the substances can partly explain the effects of the additives on the crystallization of the solid forms. The additives that selectively promoted the crystallization of form I are the ones with d T and d H parameters similar to those of piroxicam.

In this work, process analytical technology (PAT) based approaches for controlling the polymorphism and crystal size of a nonsteroidal anti-inflammatory drug (piroxicam) during batch cooling crystallization has been investigated. Previously obtained results regarding the crystallization behavior of the different polymorphs of piroxicam in a small-scale (100 mL) crystallizer have been used to design and to initiate the control approach described in this paper. The results of the present work demonstrated the challenge of reproducing the crystallization process with respect to the product polymorphism at different scales. The solute concentration has been proved to be a critical parameter in determining the polymorphism of piroxicam in the small-scale crystallization experiments; however, the same operation parameters could not yield the same polymorph in the crystallization in 2 L crystallizers. Both direct nucleation control (DNC) and supersaturation control (SSC) have been proven to be effective at controlling the polymorphism of piroxicam in seeded cooling crystallization; furthermore, applying DNC also improved the particulate properties (larger crystal size).

Recently, new insights into crystallization prior to actual nucleation have shown interesting results for drugs showing differences in hydrogen bonding or orientation in various polymorphic forms. On the basis of this concept, piroxicam was chosen as a model compound because the two common forms, I and II, show hydrogen bonding between different parts of the molecules and differences in the orientation of molecules in the crystal lattice. The goal of this work is to explore how various methods of controlling polymorphism during production could be employed. The mechanisms behind the nucleation were also explored, and new insights into polymorphic control are documented and discussed. The crystal landscape was mapped for cooling crystallization of piroxicam from acetone/water mixtures (0.5 K/min) and for antisolvent crystallization from acetone with water as the antisolvent. Varying cooling rates and the use of seeding were used to determine if the system was controlled by a single nucleation event or if the initial form was not the determining factor for the produced form. Finally, the use of soluble additives have previously been found to impact the polymorphic form and was thus employed to impact the nucleation rate as well as the formation of the solid forms in batch cooling crystallization.

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