Category: Formulation and Quality
Purpose: Celecoxib (CEL) is a COX-2 selective nonsteroidal anti-inﬂammatory drug for treating pain and inﬂammation associated with arthritis. It is a BCS class II drug with low solubility and high permeability. The mechanical property of marketed form III CEL is exceptionally elastic and renders poor flow properties for satisfactory tablet manufacture. The goal of this work is to improve processability and manufacturability of CEL, through forming two novel solvates with N-Methyl-2-Pyrrolidone (NMP). The solid-state properties of the two solvates including physical stability, were characterized to guide their robust preparation.
Methods: The mono-NMP solvate of CEL was prepared by slow evaporation method at room temperature. The di-NMP solvate can be obtained by slurry method at room temperature or by cooling of a saturated solution of CEL in NMP. Solvent-mediated phase transformation from the di-NMP solvate to mono-NMP solvate was characterized. The thermodynamic phase transition temperature was bracketed by suspending mixtures of the two forms in NMP at different temperatures, where equilibrium solid phases were identified by Powder X-Ray Diffraction (PXRD) to determine the more stable crystal form at each temperature. Thermal properties were characterized by Differential Scanning Calorimetry, Thermogravimetric Analysis, and hot-stage microscopy. Intermolecular interactions and mechanical properties were studied by Infrared Spectroscopy (IR), and nanoindentation, respectively. Crystal structures were solved by single crystal X-ray diffractometry and analyzed to explain pertinent solid-state properties.
Results: The mono-NMP solvate and di-NMP solvate were hexagonal and rod-shaped, respectively. Both exhibited improved flow properties than CEL due to their more equidimensional shapes. The Hardness and Elastic modulus of the disolvate were lower than those of the monosolvate. Hot stage microscopy revealed complex series of events when the di-NMP crystals were heated while covered with silicone oil, i.e., desolvation of the di-NMP followed by its dissolution and simultaneous growth of the monosolvate mediated by the NMP from the desolvation. The phase transition temperature (Tt) was between 35 °C and 36 °C, where the disolvate was thermodynamically more stable below 35 °C while the monosolvate was more stable above 36 °C. The disolvate converted to the monosolvate at 25 °C under vacuum. In the monosolvate, the NMP molecules interact strongly with CEL molecules through two strong N-H…O hydrogen bonds, and further forming a hydrogen bonded tetramer consisting of two NMP and two CEL molecules (Figure 1a). In the disolvate structure, one NMP molecule still interacts with one CEL molecule through two strong N-H…O hydrogen bonds, with slight rotation in the sulfonamide group of CEL. The second NMP molecule does not form any strong hydrogen bonds with CEL (Figure 1b) and loosely fill the channels along the crystallographic b axis (Figure 1c). These structural differences explain the conversion of the disolvate to monosolvate under vacuum and upon heating as well as the different mechanical properties.
Conclusion: We report two new solvated phases of CEL, mono-NMP and di-NMP, and their solid-state properties. The transition temperature between the two phases was bracketed 35 – 36 °C in NMP solution, below which the di-NMP is more stable. The different thermal and mechanical properties of the two crystal forms were explained from their crystal structures.