Amorphous Salts Solid Dispersions of Celecoxib: Enhanced Biopharmaceutical Performance and Physical Stability

Abstract

Numerous amorphous solid dispersion (ASD) formulations of celecoxib (CEL) have been attempted for enhancing the solubility, dissolution rate, and in vivo pharmacokinetics via high drug loading, polymer combination, or by surfactant addition. However, physical stability for long-term shelf life and desired in vivo pharmacokinetics remains elusive. Therefore, newer formulation strategies are always warranted to address poor aqueous solubility and oral bioavailability with extended shelf life. The present investigation elaborates a combined strategy of amorphization and salt formation for CEL, providing the benefits of enhanced solubility, dissolution rate, in vivo pharmacokinetics, and physical stability. We generated amorphous salts solid dispersion (ASSD) formulations of CEL via an in situ acid–base reaction involving counterions (Na+ and K+) and a polymer (Soluplus) using the spray-drying technique. The generated CEL-Na and CEL-K salts were homogeneously and molecularly dispersed in the matrix of Soluplus polymer. The characterization of generated ASSDs by differential scanning calorimetry revealed a much higher glass-transition temperature (T g) than the pure amorphous CEL, confirming the salt formation of CEL in solid dispersions. The micro-Raman and proton nuclear magnetic resonance spectroscopy further confirmed the formation of salt at the −SO position in the CEL molecules. CEL-Na-Soluplus ASSD exhibited a synergistic enhancement in the aqueous solubility (332.82-fold) and in vivo pharmacokinetics (9.83-fold enhancement in the blood plasma concentration) than the crystalline CEL. Furthermore, ASSD formulations were physically stable for nearly 1 year (352 days) in long-term stability studies at ambient conditions. Hence, we concluded that the ASSD is a promising strategy for CEL in improving the physicochemical properties and biopharmaceutical performance.

Combining enabling formulation strategies to generate supersaturated solutions of delamanid: In situ salt formation during amorphous solid dispersion fabrication for more robust release profiles

“…Historically, salt formation has been used to improve the crystallinity of a given drug. There are relatively few studies on improving glass forming ability through salt formation [10] , [19] , [50] , although just as counterions can promote formation of an ordered crystal lattice, it can be anticipated that they can equally effectively disrupt the lattice, depending on the nature of the counterion, and the site of ionization. For delamanid, the site of ionization is the piperidine ring.…”

“…Preparation of amorphous solid dispersion of salts has been suggested as a promising strategy to combine the benefits of amorphization and salt formation for improved dissolution and stability against crystallization during storage [10] . For delamanid, using certain sulfonic acid salts in the fabrication of ASDs led to a clear improvement in the attainable drug loading where crystal-free systems could be obtained immediately following preparation.…”

“…Salt formation is a commonly employed strategy to alter the physicochemical properties of ionizable active pharmaceutical ingredients, including hygroscopicity, melting point and dissolution rate [8] , [10] , [11] , [12] . Salt formation to produce crystalline salts is an extremely common approach to improve the developability of candidate drugs.…”

Comparative analysis of drug-salt-polymer interactions by experiment and molecular simulation improves biopharmaceutical performance

“…S3b-g). These T g values range from 71.5 to 108.8 °C and are higher than the T g of pure amorphous CEL (59.8 °C), indicating better stability of the formulations [27] . The T g values of the ASSDs are higher than those for the ASDs, with the highest value being observed for the CEL-K-PVP-VA ASSD.…”

“…The interaction of CEL with the counterion can also be observed in the crystal structure of the CEL-Na + salt [46] . The weaker electrostatic interaction between CEL and the K + counterion is due to the larger ionic radius and lower charge density of K + as compared to the Na + counterion [27, 47] .…”