(W1030-12-83) Developing Microspherical Celecoxib Amorphous Solid Dispersion Using Electrospraying for Dissolution Enhancement

Purpose: Celecoxib (CEL), a nonsteroidal anti-inflammatory drug (NSAID) and selective cyclooxygenase-2 (COX-2) inhibitor, provides relief for patients suffering from osteoarthritis and rheumatoid arthritis with less gastrointestinal discomfort compared to conventional NSAIDs [1,2]. However, the extremely low aqueous solubility of CEL greatly limits its systemic absorption, resulting in diminished oral bioavailability. To address this challenge, we have prepared a Soluplus®-celecoxib (SEL-CEL) amorphous solid dispersion (ASD) using the electrospray technique, in which Soluplus® (SOL) is the carrier and solubilizer excipient. The ASD significantly increased the aqueous solubility of CEL, reflected by a 5.4-fold rise in maximum concentration compared to crystalline CEL. The electrospray is capable of producing micro/nanoscale polymeric spheres at room temperature and atmosphere pressure, offering a promising alternative to conventional hot melt extrusion (HME) [3] and spray drying (SD) methods [4]

Methods: CEL and SOL were dissolved into dimethyl chloride (DCM) at a weight ratio of 19:81 to create a 9% visually uniform solution for electrospraying. A comparable 9% SOL-DCM solution was also prepared for electrospraying as a reference. The electrospray process was conducted using an in-house setup at approximately 21°C and atmosphere pressure, with the solution injection rate of 0.5 ml/h. The produced ASD was characterized using differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD) and scanning electron microscopy (SEM). The drug release behavior for both electrosprayed ASD and pure CEL in the phosphate buffer solution (PBS, pH 7.4) with 0.25 w/v% sodium dodecyl sulfate (SDS) was investigated. The CEL loading efficiency of the ASD was also analyzed.

Results: The microspherical ASD was successfully prepared by electrospraying. SEM images revealed monodisperse microspheres with smooth surfaces, measuring 2-3 μm wide for both ASD and pure SOL particles (Figures 1a-b). DSC analysis verified that the CEL melting peak at 165°C, typically present in the crystalline form, was notably absent in the ASD (Figure 1c), thereby confirming its transformation into an amorphous state. The XRPD pattern of pure CEL exhibited characteristic 2θ peaks at 5.35°, 10.70°, 16.08°, 21.49° and 26.98° [5], such peaks were absent in the ASD (Figure 1d). In terms of the drug release profile (Figure 2 and Table 1), the electrosprayed SOL-CEL ASD markedly enhanced the dissolution rate of crystalline CEL, as evidenced by a 6.4-fold increase in dissolution efficiency [6] compared to crystalline CEL at pH 7.4. The ASD also exhibited a high drug loading efficiency of 88.14 ±0.10 %, indicating effective CEL loading during the electrospraying process (Table 1).

Conclusion: Our study demonstrates the successful fabrication of SOL-CEL microsphere via electrospray. DSC and XRPD analyses suggest that CEL is well dispersed in the SOL matrix, transforming crystalline CEL into the amorphous form. This ASD state significantly enhanced the CEL dissolution compared to its crystalline counterpart. The electrospray-based ASDs offers a promising approach for improving oral bioavailability of CEL and other poorly water-soluble drugs, due to their mild preparation condition and flexibility to adjust for specific drug properties.

References: 1. Wang Q, Yang X, Gu X, Wei F, Cao W, Zheng L, et al. Celecoxib nanocrystal-loaded dissolving microneedles with highly efficient for osteoarthritis treatment. Int J Pharm [Internet]. 2022;625:122108.
2. Brune K, Hinz B. Selective cyclooxygenase-2 inhibitors: Similarities and differences [Internet]. Scand. J. Rheumatol. 2004. p. 1–6.
3. Andrews GP, Qian K, Jacobs E, Jones DS, Tian Y. High drug loading nanosized amorphous solid dispersion (NASD) with enhanced in vitro solubility and permeability: Benchmarking conventional ASD. Int J Pharm [Internet]. 2023;632:122551.
4. Bhujbal S V., Mitra B, Jain U, Gong Y, Agrawal A, Karki S, et al. Pharmaceutical amorphous solid dispersion: A review of manufacturing strategies. Acta Pharm Sin B [Internet]. 2021;11:2505–36.
5. Tran P, Nguyen TN, Park JS. Co-carrier-based solid dispersion of celecoxib improves dissolution rate and oral bioavailability in rats. J Drug Deliv Sci Technol [Internet]. 2023;79:104073.
6. Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci [Internet]. 2001;13:123–33.

Figure 1. Electrosprayed ASD characterization: a) SEM images of electrosprayed SOL microspheres; b) SEM images of ASD microspheres; c) DSC curves of pure CEL, pure SOL and electrosprayed SOL-CEL ASD; d) XRPD patterns of pure CEL, pure SOL and electrosprayed SOL-CEL ASD. Magnification for main and insert SEM images are 1,000X and 30,000X, respectively; the scale bar for main and insert SEM images are 50 and 1 μm, respectively.

Figure 2. Drug release profile comparison of pure CEL and electrosprayed SOL-CEL ASD: a) CEL concentration versus time; b) accumulative release of CEL versus time.

Table 1. Summary of electrospraying solution formulations and drug release study results.