(T1430-05-28) Modification of Microenvironmental pH of Nanoparticles for Enhanced Solubility and Oral Bioavailability of Poorly Water-Soluble Celecoxib

Purpose: This study aimed to develop a novel pH-modified nanoparticle with improved solubility and oral bioavailability of poorly water-soluble celecoxib by modifying the microenvironmental pH.

Methods: After assessing the impact of hydrophilic polymers, surfactants and alkaline pH modifiers on the drug solubility, copovidone, sodium lauryl sulfate (SLS) and meglumine were chosen. The optimal formulation of solvent-evaporated, surface-attached and pH-modified nanoparticles composed of celecoxib/copovidone/SLS/meglumine at weight ratios of 1:1:0.2:0, 1:0.375:1.125:0 and 1:1:1:0.2:0.02, respectively, were manufactured using spray drying technique. Their physicochemical characteristics, solubility, dissolution and pharmacokinetics in rats were evaluated compared to the celecoxib powder.

Results: The solvent-evaporated and pH-modified nanoparticles converted a crystalline to an amorphous drug, resulting in a spherical shape with a reduced particle size compared to celecoxib powder. However, the surface-attached nanoparticles with insignificant particle size exhibited the unchangeable crystalline drug. All of them gave significantly higher solubility, dissolution, and oral bioavailability than celecoxib powder. Among them, the pH-modified nanoparticles demonstrated the most significant improvement in solubility (approximately 1600-fold) and oral bioavailability (approximately 4-fold) compared to the drug powder owing to the alkaline microenvironment formation effect of meglumine and the conversion to the amorphous drug.

Conclusion: Thus, the pH-modified nanoparticle system would be a promising strategy for improving the solubility and oral bioavailability of poorly water-soluble and weakly acidic celecoxib.

Acknowledgements: This work was supported by the National Research Foundation of South Korea (NRF) grants funded by the South Korean government (MEST) (No. 2022R1A2C2004197 and RS-2023-00208448).


Scanning electron micrographs: (A), Celecoxib powder (×5,000); (B), solvent-evaporated nanoparticle (×2,000); (C) solvent-evaporated nanoparticle (×5,000); (D), surface-attached nanoparticle (×2,000); (E) surface-attached nanoparticle (×5,000); (E), pH-modified nanoparticle (×2,000) (F), pH-modified nanoparticle (×5,000).


(A), Differential scanning calorimetry (DSC) thermograms and (B), powder X-ray diffraction (PXRD) patterns: (a) celecoxib powder, (b) physical mixture (celecoxib/copovidone/SLS=1:1:1, weight ratios), (c) solvent-evaporated nanoparticles, (d) surface-attached nanoparticles, (e) pH-modified nanoparticles. (C), Fourier transform infrared (FTIR) spectra: (a) celecoxib powder, (b) copovidone, (c) SLS, (d) meglumine, (e) solvent-evaporated nanoparticles, (f) surface-attached nanoparticles and (g) pH-modified nanoparticles. (D), Particle size distribution. Each value is expressed as the mean ± SD (n=3). *p < 0.05 compared to the diameter at the 50th percentile (D50) of other nanoparticles.


Solubility and dissolution rate of celecoxib-loaded pH-modified nanoparticles: (A), Solubility of all nanoparticles; (B), Dissolution of all nanoparticles; (C), Plasma concentration-time profiles of celecoxib in rats following oral administration. Each value is expressed as the mean ± SD (n=6). *p < 0.05 compared to other formulations.