Salt and Cocrystal Forms of Diclofenac with Pyridine and Pyridone Coformers for Improving Drug Bioavailability

Abstract

The modification of the physicochemical properties of diclofenac (DCF), a Biopharmaceutics Classification System (BCS) class II drug, remains a primary objective in pharmaceutical crystal engineering. This study examines the supramolecular landscapes of DCF solid-state forms crystallized using 2-aminopyridine (2APY), 3-aminopyridine (3APY), 4-aminopyridine (4APY), 2-pyridone (2PY), 3-hydroxypyridine (3HPY), and 4-pyridone (4PY). The crystalline binary solids were characterized using single-crystal X-ray diffraction (SC-XRD) analysis. The salt, cocrystal, and continuum states were analyzed based on ΔpKa values and the difference between the carbonyl bond distances (ΔDCO) of the carboxylic acid group in DCF. It was observed that DCF·2APY and DCF·3APY cocrystallized in Z″ = 3, where the asymmetric unit contains one neutral DCF, an anionic DCF, and a cationic 2APY or 3APY molecule (Z″ is the number of distinct molecules in the asymmetric unit). DCF·4APY formed monohydrate and hemihydrate salts. DCF·2PY and DCF·4PY formed a cocrystal in a 1:1 stoichiometry of DCF and the coformer. DCF·3HPY showed a borderline case of salt and continuum states by X-ray diffraction and based on ΔDCO and ΔpKa difference values. The thermodynamic properties of the structurally characterized solid forms were evaluated by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Solubility and dissolution analysis furnished the stability of DCF·2APY (1:1) in acidic and neutral media and showed an enhancement in the equilibrium solubility of ∼23-fold and ∼28-fold, respectively. However, DCF·2APY (2:1) was unstable in an acidic environment but stable in a neutral medium with an improved equilibrium solubility of ∼32-fold. Dissolution and permeability under a pH 7 buffer showed significant improvement compared to DCF free acid, where the permeability order of different solid forms was observed in the order of their dissolution rate. The highest dissolution rate and permeability/flux were observed for DCF·2APY (2:1), whereas cocrystals (DCF·2PY and DCF·4PY) showed the lowest dissolution rate and flux but still higher than that of DCF free acid. These experiments demonstrate the advantage of DCF cocrystals and salts with APY, HPY, and PY coformers over DCF free acid in terms of dissolution rate and passive permeability/flux. Furthermore, DCF·2APY (2:1), with the highest dissolution rate and flux along with 66.6% DCF and 33.3% excipient in a single crystalline phase, suggests the possibility of high-payload cocrystal engineering of DCF with 2APY.