Enabling Direct Compression Tablet Development Of Celecoxib Through Solid State Engineering

Abstract

Tablets are the most desirable solid oral dosage form for patients. Direct compression (DC) tablet formulation is the most economical, robust and efficient way of tablet manufacture. Being sensitive to properties of the Active Pharmaceutical Ingredient (API), direct compression tablet formulation is not available for the high dose non-steroidal anti-inflammatory drug, celecoxib (CEL) due to the undesirable properties of the commercial solid form of CEL, including low bulk density, poor flowability and tablet lamination issues. The solid form used in commercially available CEL capsules is a polymorph of CEL, Form III. Form III CEL is a needle shaped crystal, which is exceptionally elastic. This high elasticity, verified by nanoindentation and three-point bending tests, is unfavorable for good tablet quality and performance during high speed tableting. Through understanding the molecular interactions by analyzing the CEL crystal structure, a structural model for high elasticity is built and validated by Raman spectroscopy. Interlocked molecular packing without slip plane and the presence of isotropic hydrogen bond network are major structural features responsible for both the exceptional elastic flexibility and high stiffness of the CEL crystal. CEL Form III exhibits unsatisfactory flowability and tablet lamination issues for DC tablet manufacturing. Pharmaceutically acceptable solvates of CEL offer better flow, compaction and dissolution properties than CEL Form III. Two stoichiometric solvates of CEL and N-methyl-2-pyrrolidone (NMP) are extensively characterized and examined, which establishes a clear crystal structure-property relationship essential for crystal engineering of CEL. Through crystal engineering, a DC tablet formulation of CEL is successfully developed using the dimethyl sulfoxide (DMSO) solvate of CEL. This pharmaceutically acceptable solvate is highly stable and also exhibited much improved manufacturability compared to CEL Form III, including better flowability, lower elasticity and bulk density (superior tablet quality) as well as better dissolution performance. As a Class II drug in the biopharmaceutics classification system with low solubility and high permeability, the high dose of CEL is partially attributed to its limited solubility. Amorphous CEL, although providing solubility advantages as the thermodynamically high energy state, is unstable and prone to crystallization. The study of crystal growth of amorphous CEL reveals a fast glass-to-crystal growth mode at room temperature with a surface-enhanced mechanism. This paves the way for future development of a stable amorphous solid dispersion tablet product of CEL with improved dissolution performance and tablet manufacturability. In summary, by understanding the structural origin of undesired properties of CEL, successful development of the most patient-compliant tablet dosage form by direct compression can be achieved. This sets an excellent example of utilizing a solid state engineering approach to effectively overcome challenges encountered in direct compression tablet development.