Direct Compression Development of Celecoxib Tablet through Solid State in Dimethyl Sulfoxide

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 celecoxib, including low bulk density, poor flowability and tablet lamination issues. The solid form used in commercially available celecoxib capsules is a polymorph of celecoxib, Form III. Form III celecoxib is a needle shaped crystal, which is exceptionally elastic. This high elasticity, verified by nano indentation 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 celecoxib 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 celecoxib crystal. celecoxib Form III exhibits unsatisfactory flowability and tablet lamination issues for DC tablet manufacturing. Pharmaceutically acceptable solvates of celecoxib offer better flow, compaction and dissolution properties than celecoxib Form III. Two stoichiometric solvates of celecoxib and N-methyl-2-pyrrolidone (NMP) are extensively characterized and examined, which establishes a clear crystal structure-property relationship essential for crystal vi engineering of celecoxib. Through crystal engineering, a DC tablet formulation of celecoxib is successfully developed using the dimethyl sulfoxide (DMSO) solvate of celecoxib. This pharmaceutically acceptable solvate is highly stable and also exhibited much improved manufacturability compared to celecoxib 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 celecoxib is partially attributed to its limited solubility. Amorphous celecoxib, although providing solubility advantages as the thermodynamically high energy state, is unstable and prone to crystallization. The study of crystal growth of amorphous celecoxib 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 celecoxib with improved dissolution performance and tablet manufacturability. In summary, by understanding the structural origin of undesired properties of celecoxib, 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. Key words: CEL – Celecoxib, API (Active Pharmaceutical Limited),Raman Spectroscopy dimethyl sulfoxide (DMSO),etc