Formation of Piroxicam Polymorphism in Solution Crystallization: Effect and Interplay of Operation Parameters

Abstract

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.

Polymorphic behavior of isonicotinamide in cooling crystallization from various solvents

“…But since a change in initial concentration also changes the nucleation temperature, it is difficult to determine which of the two has the largest impact. Similar result has though, been observed in our previous work [15] where the crystallization of piroxicam from different acetone-water mixtures was investigated. The results showed a well-defined landscape of the two polymorphs of piroxicam depending on the initial concentration, where form 2 was produced at high solute concentrations and form 1 was formed at low concentration ranges as long as the acetone mass fraction of the solvent was kept below 95%.…”

“…Although several works showed a link between the structure of the building units formed by the self-association of the molecules and the polymorphism of the nucleated crystals, we have discovered the complex nature of this structural link in the previous work regarding the crystallization of piroxicam. It has been observed in our previous work [15] that the solute concentration played a significant role in determining the polymorphism of piroxicam crystallized from acetone-water solutions.…”

“…Kulkarni et al [14] have reported the possible link between the solvent and polymorph of INA. But it has been observed in our precious work that the initial solute concentration has a big impact on the polymorphism of Piroxicam, which is a nonsteroidal anti-inflammatory drug that also shows different hydrogen bonding network and molecular orientation in different polymorphs [15]. The present work focused on developing a better understanding of the link between molecular self-association of INA in various solvents using FT-IR and Raman spectroscopy.…”

Process Analytical Tools To Control Polymorphism and Particle Size in Batch Crystallization Processes

“…It was therefore decided to use seeding to have robust control of the product polymorphism. 19 . In some cases, the monohydrate form was also found during anti solvent experiments, although in very low quantities and only at 45°C.…”

“…The form I crystals produced in the successful batch of anti solvent crystallization was used as seed crystals to investigate the feasibility of controlling the polymorphism of Piroxicam in cooling crystallization in the 2 L crystallizer system. ( It has been observed that seeding was effective for controlling polymorphism in the small scale 100 mL crystallizer 19 . For this reason seeded cooling crystallizations were conducted also to crystallize…”