Physical Stability and Solubility Advantage from Amorphous Celecoxib:  The Role of Thermodynamic Quantities and Molecular Mobility

Abstract

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.

Olfactory transport efficiency of the amorphous and crystalline manganese oxide nanoparticles

“…Возможно, гидрофиль-ность аморфных частиц выше, чем кристаллических, что, как следует из данных, полученных in vitro, может значительно увеличить интенсивность их проникновения через мукозальный слой (Lai et al, 2009). Это подтверж-дается рядом теоретических и экспериментальных ис-следований, в которых показано, что по мере уменьшения степени упорядоченности кристаллической структуры химического соединения возрастает его гидрофильность (Hancock, Parks, 2000;Gupta et al, 2004;Good, Rodríguez Hornedo, 2009;Murdande et al, 2010). Кроме того, для некоторых слаборастворимых фармпрепаратов показано, что использование более гидрофильных аморфных форм позволяет увеличить по сравнению с кристаллическими биодоступность соединения за счет увеличения концен-трации частиц в предъявляемом коллоидном растворе (Miyazaki et al, 1975;Yang et al, 2010).…”

Collective relaxation dynamics and crystallization kinetics of the amorphous Biclotymol antiseptic

“…Compared to the crystalline form, the amorphous form of API's offers the advantage of a higher solubility (Gupta et al, 2004) and bioavailability (Serajuddin, 1999). The amorphous glass state has however the disadvantage of being thermodynamically unstable against the nucleation of crystalline phases (Bhardwaj et al, 2013;Zhou et al, 2002).…”

Role of Thermodynamic, Molecular, and Kinetic Factors in Crystallization from the Amorphous State

“…In such situations the use of the amorphous state, with higher free energy and therefore higher solubility, offers a promising alternative. 2 Despite the potential benefit offered by the amorphous state, its use in solid oral dosage forms is limited, the key factor being higher instability of the amorphous form. The higher instability of the amorphous form arises from thermodynamic instability relative to the crystalline state and higher molecular mobility, leading to higher chemical degradation rates and spontaneous recrystallization.…”

“…Several researchers have attempted to correlate the crystallization tendencies of different glass formers with molecular mobility, thermodynamic properties of the amorphous matrix, molecular interactions, moisture content, and the way the amorphous state is generated. 2,6,7,[9][10][11][12][13][14][15][16][17][18] However, there is no current review describing the present state of understanding of crystallization from the amorphous state. A better understanding of the complex process of crystallization from the amorphous state is of both fundamental and practical interest.…”