Nanococrystals of Diclofenac Acid to Improve Biopharmaceutical Performance: Understanding the Key Drivers

Background: In this study, two cocrystals of diclofenac acid (DCA) with the coformers theophylline (THEO) and isonicotinamide (ISNT) were prepared. Subsequently, nanococrystals were generated from these cocrystals using a top-down wet media milling approach. Methods: Critical process parameters such as milling time, milling volume, drug loading percentage, bead volume, and dispersion media were optimized to achieve the desired particle size distribution. The nanococrystals were characterized using dynamic light scattering (DLS), polarized light microscopy (PLM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Results: In vitro dissolution studies revealed that nanococrystals of DCA-ISNT (DE_0-120 = 22.5% at pH 1.2 and DE_0-120 = 58.7% at pH 4.5) and DCA-THEO (DE_0-120 = 18.5% at pH 1.2 and DE_0-120 = 48.2% at pH 4.5) exhibited superior dissolution performance compared to DCA nanocrystals (DE_0-120 = 12.5% at pH 1.2 and DE_0-120 = 39.0% at pH 4.5), with the dissolution advantage decreasing as the pH of the medium increased. The improved dissolution behaviour was a complex interplay of factors including particle size distribution, surface wetting kinetics, exposure of hydrophilic/hydrophobic functional groups during dissolution, nanococrystal microenvironmental pH, DCA's ionization behaviour, lattice energy, and intermolecular interaction strengths. Additionally, nanococrystals exhibited a significantly higher flux rate in simultaneous gastric transfer dissolution and flux studies compared with DCA, likely due to higher apparent solubility and superior diffusion through the unstirred water layer (UWL). Pharmacokinetic studies confirmed that nanococrystals DCA-ISNT NCC (AUC_0-∞ = 3062.65 ± 526.91 ng/mL·h) outperformed DCA nanocrystals (AUC_0-∞ = 2352.53 ± 537.78 ng/mL·h), DCA-THEO NCC (AUC_0-∞ = 2222.96 ± 151.19 ng/mL·h) and the cocrystals in terms of pharmacokinetic performance. Conclusions: The findings indicate that DCA-ISNT NCC exhibited superior pharmacokinetic performance and, together with the enhanced dissolution and flux properties of the nanococrystals, demonstrates their potential for enhanced therapeutic efficacy.