An optimized commercially feasible milling technique for molecular encapsulation of meloxicam in β-cyclodextrin

Abstract

Background: The practical applicability of solid dispersions (SD) for improvement of oral bioavailability of poorly water-soluble drugs has still remained limited because of lack of feasibility for scale-up of manufacturing processes. The present research work deals with the preparation of SDs of meloxicam (MLX) with β-cyclodextrin (β-CD) by the ball-milling technique to overcome the scale-up issues.

Methods: Phase-solubility studies were conducted to analyze the influence of β-CD on solubility of MLX. In vitro dissolution studies on various complexes as well as tablets prepared on pilot scale in an industrial set up were performed and compared with the marketed products. Physicochemical characterization of optimized complexes was done using various methods to study drug-β-CD interaction.

Results: Solubility of pure MLX in water at 25°C was found to be only 9.4 µg/mL. The AL type of phase-solubility profile of MLX with β-CD [stability constant (K_1:1) = 22.056 M⁻¹ and Gibbs free energy (ΔF^o) = –7.665 KJ/mole] confirmed the solubility enhancement capability of β-CD. Milling time of 6 h was considered to be optimum and showed maximum enhancement of drug dissolution. The amorphous nature of the milled complex and mode of interaction of MLX with β-CD was confirmed by differential scanning calorimetry (DSC), x-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance spectrophotometry (¹HNMR). Tablets containing MLX-β-CD (1:1.5 M) milled complexes showed the best release (T_90% = 10.94 min) compared to the marketed products (T_90% ≥ 450 min). Stability studies performed confirmed the integrity of the amorphous complex.

Conclusion: Stable inclusion complexes of MLX-β-CD with enhanced aqueous solubility and dissolution rate were prepared by a highly efficient and controlled large-scale milling technique.

Keywords::

• Ball-milling
• tablets
• industrial scale-up
• solubility
• dissolution

Acknowledgements

The authors are grateful to Unichem Laboratories Ltd., Mumbai, Maharashtra, India, for gift sample of MLX and granting permission to conduct the pilot scale studies in their premises. Thanks are due to S.A. Chemicals Ltd., (Mumbai, Maharashtra, India), for generous supply of β-CD, respectively.

Declaration of interest

The authors report no conflicts of interest.