2024 AIChE Annual Meeting

Thermodynamic and Kinetic Analysis of Impurity Retention in Dyed Pharmaceutical Crystals

Impurities in the crystal structure of an active pharmaceutical ingredient (API) can influence its properties, such as stability and solubility. Conventional methods to measure composition anisotropy or impurity concentration across different crystal faces are often destructive or require intricate calibration. By introducing colored impurities, such as dyes, visibility into impurity incorporation can be achieved, offering a non-destructive alternative based on model compounds.

The use of this technique is illustrated through thermal cycling of a saturated mother liquor with dye impurities, showing how composition anisotropy of single crystal can be analyzed over each cycle of dissolution and regrowth. Two host/guest systems were studied: acetaminophen with curcumin and potassium sulfate with acid fuchsin, under thermal cycling conditions between 25°C and 35°C to examine impurity distribution and dissolution-regrowth behavior. By using red-to-green pixel intensity ratios, from images taken under controlled lighting conditions, it can be used to assess impurity distribution across the crystal lattice without the destruction of the crystal samples.

When dye impurities are introduced, the thermodynamic and kinetic properties of crystallization become apparent during thermal cycling of each host/guest system. Thermal cycling alternates between dissolution and regrowth, revealing differences in impurity retention due to thermodynamic equilibrium and growth kinetics. In the acetaminophen/curcumin system, impurity-rich regions dissolve preferentially due to thermodynamic instability, leaving behind cleaner faces that serve as favorable sites for regrowth. This results in mass loss and reduced impurity retention, driven by the system's kinetics favoring cleaner surfaces during recrystallization. In contrast, the potassium sulfate/acid fuchsin system shows slower dissolution kinetics, maintaining most of its mass during cycling. However, regrowth leads to increased impurity incorporation in the cleaner crystal faces, as thermodynamic conditions promote impurity uptake in these regions. This system’s slower impurity incorporation kinetics highlights a more gradual impurity retention process compared to acetaminophen.

The use of colored impurities enables non-destructive analysis of composition anisotropy, providing valuable insights into crystallization behaviors. These findings demonstrate the distinct mechanisms of impurity retention in different systems, emphasizing the importance of understanding the interplay between thermodynamics and kinetics to optimize crystallization processes in pharmaceutical applications.