Development, optimization and in-vivo pharmacokinetic evaluation of flubiprofen nanocrystal tablets for efficient chronotherapy against rheumatoid arthritis

In an effort to enhance drug solubility for buccal mucosal delivery, various strategies such as nanoemulsions, cyclodextrin inclusions, and solid dispersions have been explored, but these methods often face limitations. An emerging solubilization technology, drug nanocrystals, offers a promising alternative due to their high drug loading capacity and scalability for large-scale production. The current study aimed to create solid nanocrystals of flurbiprofen (FP-NC) through a wet milling process to significantly improve water solubility, regardless of pH, and consequently enhance bioavailability. FP-NC was further used to formulate tablets and compressed coatings with carboxymethyl xanthan gum (CXG) and sodium alginate (SA). The compression coating process has been optimized using Quality by Design principles. Utilizing the desirability approach, we identified an optimal formulation with 56.05 mg of CXG, 74.96 mg of SA, and a coating material weight of 249.98 mg. This formulation achieves desired chronotherapeutic characteristics with a lag time (LT) of 5.99 h and T90% of 11.48 h. We conducted in-vitro and ex-vivo drug release studies and compared them with in-vivo pharmacokinetic parameters, employing level A in-vitro in-vivo correlation (IVIVC). Notably, the continuous ex-vivo method exhibited a stronger correlation compared to traditional in-vitro drug release assessments. This suggests that our novel drug release system using the NC compressed coating technique holds promise for achieving chronotherapeutic effects with improved bioavailability.