Physical stability and solubility advantage from amorphous celecoxib: the role of thermodynamic quantities and molecular mobility.
Glassy pharmaceuticals, characterized by excess thermodynamic properties, are theoretically more soluble than their crystalline counterparts. The practical solubility advantage of the amorphous form of celecoxib (CEL) is lost due to its proclivity to lose energy and undergo solvent-mediated devitrification. Theoretical assessment of solubility advantage using differences in isobaric heat capacities (Cp) revealed a 7-21-fold enhancement in the solubility of the amorphous form over that of the crystalline state of CEL. The present study attempts to unveil these differences between experimental and theoretical solubility using thermodynamic parameters such as free energy, enthalpy, and entropy. Amorphous CEL exhibited 1.3-1.5 times enhancement in Cp over that for the crystalline form. The zero and critical molecular mobility regions, represented by Kauzmann temperature (TK) and glass transition temperature (Tg), were found to lie near 246 and 323 K, respectively, for amorphous CEL. The fictive temperature (Tf), an indicator of the configurational entropy of glass, was determined for glassy CEL, signifying the retention of considerable molecular mobility in the glassy phase that may favor nucleation even below Tg. Further, the estimation of various thermodynamic quantities and strength/fragility parameters (D = 11.5 and m = 67.0) postulated the classification of glassy CEL into moderately fragile liquid, as per Angell's classification. A comprehensive understanding of such thermodynamic facets of amorphous form would help in rationalizing the approaches toward development of stable glassy pharmaceuticals with adequate solubility advantage.
Gupta
Piyush
P
Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research, Sector 67, Phase X, S.A.S. Nagar, Punjab-160062, India.
Chawla
Garima
G
Bansal
Arvind K
AK
D000068579:Celecoxib; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003460:Crystallization; D011720:Pyrazoles / Q000737:chemistry*; D012995:Solubility; D013449:Sulfonamides / Q000737:chemistry*; D013816:Thermodynamics
D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib