Nucleation During Storage Impeded Supersaturation in the Dissolution Process of Amorphous Celecoxib

Abstract

The aqueous solubility of active pharmaceutical ingredients (APIs) is one of the most critical factors in determining the absorption of orally administered drugs. Amorphization of API may offer better drug absorption than the crystalline state owing to enhanced solubility. However, if crystal nuclei are formed during storage, they may develop into crystals upon contact with water, thus limiting the dissolution advantage. In an earlier study, we found that the nuclei of amorphous celecoxib (CEL) could be formed at freezing temperatures (FT) without further crystal growth. Following this finding, we compared the dissolution performances of amorphous CEL annealed at room temperature (RT, 25 °C) or FT (−20 °C). We found that only the RT-annealed CEL could achieve a supersaturated state effectively during the dissolution process, which could be explained by the fast conversion of the FTannealed amorphous CEL to a crystalline state owing to the presence of nuclei. Investigation of the residual solids revealed that supersaturation could be maintained for a while after the appearance of the crystals, which could be explained by heterogeneous nucleation and competition between the dissolution of amorphous parts and crystallization. In addition, a new crystalline form of CEL was observed during dissolution.

Crystallinity: A Complex Critical Quality Attribute of Amorphous Solid Dispersions

“…Grown crystals may have higher polymer concentration in the immediate vicinity of nucleated crystal, where the API has been depleted due to incorporation into the nucleated crystals . Nucleation events need not be detectable by common methods in order to have significant product performance impact. , …”

Influence of Nucleation on Relaxation, Molecular Cooperativity, and Physical Stability of Celecoxib Glass

“…In fact, the nucleated CEL glass failed to form a supersaturated state after suspension of the glass in aqueous media, although it was observed for the non-nucleated glass. 19 In this study, we evaluated the influence of nucleation on glass dynamics in comparison with the non-nucleated glass with emphasis on their relaxation, molecular cooperativity, and crystallization behaviors.…”

“…Glasses with or without nuclei may exhibit different performances, even though they are characterized the same using conventional evaluation methods, including X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). In fact, the nucleated CEL glass failed to form a supersaturated state after suspension of the glass in aqueous media, although it was observed for the non-nucleated glass . In this study, we evaluated the influence of nucleation on glass dynamics in comparison with the non-nucleated glass with emphasis on their relaxation, molecular cooperativity, and crystallization behaviors.…”