(M1330-01-02) Preparation and Evaluation of Celecoxib Nanosuspension for Enhancing Its Solubility

Purpose: Nanosuspensions of celecoxib (CEL) crystal, a BCS class II selective cyclooxygenase-2 inhibitor, were prepared by solvent exchange method using different stabilizers and polymers to enhance CEL solubility and dissolution rate. CEL suspensions transformed into different dosage forms: CEL suspensions were employed and evaluated as injectable formulations for systemic pain management and spray-dried/lyophilized CEL suspension powder forms were prepared for the transformation into tablets.

Methods: Solubility screening - Solubility screening of CEL in various solvents was carried out at room temperature. Briefly, 100 mg of CEL was added in a 1.5 mL tube. Then 0.1 mL of solvent was added and vortexed for 5 min and followed by sonication for 5 min. Samples were visually checked whether CEL was dissolved, solvent was kept adding up to 1.5 mL. Determination of CEL solubility - Excess of CEL (150 mg) and solvent were mixed into a centrifuge tube. The samples were loaded into a rotator mixer and shaken at 50 rpm for 72 h. Samples were ultracentrifuged and the amount of dissolved CEL was analyzed by high-performance liquid chromatography. Preparation of celecoxib nanosuspensions - CEL suspensions were prepared by the solvent-exchange method. CEL dissolved in solvent was added to aqueous solution of stabilizers. Characterization of CEL suspensions - Characterization of the prepared CEL suspensions were performed using different techniques: particle size analysis (Dynamic Light Scattering, Powder Laser Diffraction), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), fourier transform infrared (FTIR) spectroscopy - attenuated total relectance (ATR), X-ray powder diffraction (XRD). In vitro drug release study of CEL nanosuspensions - Lyophilization/Spray drying preparation of CEL nanosuspensions powder/granules

Results: Solubility of CEL in water and solvents at room temperature - The solubility of CEL in water is very low, relatively low in ethanol, while solubility in PEG is higher and highest in Transcutol HP. Solubilities in PEG 400, PEG 300 and PEG 200 are not significantly different. The selection of solvent was performed with respect to CEL’s solubility, because of too low solubility of CEL in solvent, nanosuspension would not be enabled. Preparation of CEL nanosuspension - The water miscibility of the solvent is determining factor on the process efficiency. CEL is highly soluble in Transcutol HP which is water miscible. Stabilizers screening was performed. Sodium lauryl sufate (SLS) and Tween® 80 were used as stabilizer(s) to help forming nanoparticles. Povidone (PVP) K12 and PVP K30 were combined with SLS in order to reduce particle size and prevent aggregation of small particles. CEL suspension characterization - Particle size analysis: Raw CEL particle size (3.13 μm) ranges from 2.62 to 11.2 μm. The size of the CEL nanoparticles in CEL suspension is approximately 10 times smaller. Stabilization with SLS: F1 (1092.3 nm) and F2 (989 nm) were further evaluated as injectable formulations of CEL. In agreement with particle size analysis results, SEM images of F1 and F2 showed similar particle size range (600 – 1000 nm). Stabilization with Tween 80: F3 and F4 were subjected to transform to the form of lyophilized/spraying drying powder/granules. The average particle size obtained after lyophilization was approximately 3 times greater than before lyophilization. The average spray dried particle size was almost twice greater than before spray drying. DSC, ATR-FTIR analysis: DSC, ATR-FTIR results showed no interaction between CEL, surfactant(s) and polymer(s). PXRD analysis: PXRD pattern was detected and compared to that of raw CEL, the crystallinity was maintained, no amorphous phase was found. Dissolution test: CEL nanosuspensions were able to release 100% of CEL after 5 days. On the other hand, due to poor solubility, cumulative CEL released from raw CEL sample was only 60% in 5 days. Lyophilized/Spray dried CEL nanosuspension powder/granules was subjected to tableting and dissolution studies of CEL from lyophilized/spray dried CEL nanosuspension powder/granules (paddle method), dissolution studies of CEL nanosuspension tablets (paddle method) are meant to be performed. The effect of stabilizers and polymers are yet to be investigated.

Conclusion: 1.Poorly water soluble CEL was successfully prepared using an solvent exchange with surfactant or polymer stabilizer. The resulted CEL nanosuspensions can be employed as injectable formulations for systemic pain management or can be further processed with spray drying and/or lyophilization for the transformation into tablets. 2.The choice of solvent, surfactant(s) and polymer(s) has important effects on the particle size of nanosuspension particles, this can also affect the release patterns of the obtained formulations. In this study, nanosuspension strategy and these findings indicated the suitability of formulation and formulation procedure for preparation of nano-sized poorly water soluble drug with significant improvement of the in vitro dissolution rate, and thus possibly improve their bioavailability. *Further studies are necessary to evaluate these CEL nanosuspensions formulations.


The solubility of CEL was determined in water (3-7 µg/ml) and in different organic solvents.


SEM images of CEL nanosuspensions particles


In vitro drug release profile of F1 & F2 injectable formulations compared to raw CEL (n = 3)