Prediction of Liquid-Liquid Phase Separation at the Dissolving Drug Salt Particle Surface

During the dissolution of drug salt particles, liquid-liquid phase separation (LLPS) of a free form can occur within the unstirred water layer (UWL) of the particles (UWL-LLPS). Theoretically, UWL-LLPS occurs when the free form concentration at the salt particle surface (C₀) exceeds the intrinsic LLPS concentration (S₀^LLPS) of the free form. In the present study, we attempted to predict UWL-LLPS based on the intrinsic physicochemical properties of drugs. Cyproheptadine hydrochloride (CPH-HCl), diclofenac sodium (DCF-Na), papaverine hydrochloride (PAP-HCl), and propafenone hydrochloride (PRF-HCl) were selected as model drug salts. The pH₀ and C₀ values at pHs 4.0-9.5 (citric acid, phosphoric acid, and boric acid, buffer capacity = ca. 4 mM/ΔpH) were calculated using the pK_a, solubility product (K_sp), and diffusion coefficient (D) of a drug. S₀^LLPS was measured using the pH-shift method. UWL-LLPS was predicted to occur when C₀ ≥ S₀^LLPS. The prediction result was then compared with UWL-LLPS observed at each pH by polarized light microscopy (PLM). The pH-LLPS concentration (S_pH^LLPS) profile of each drug was also measured. UWL-LLPS was approximately correctly predicted for CPH-HCl, DCF-Na, and PRF-HCl. However, UWL-LLPS was not observable when C₀ was close to S₀^LLPS. Furthermore, UWL-LLPS was not accurately predicted in the case of PAP-HCl. The pH-S_pH^LLPS profile of PAP did not follow the Henderson-Hasselbalch equation, probably because of the formation of cationic aggregates. In conclusion, UWL-LLPS was approximately predictable for drug salts using their intrinsic physicochemical properties (K_sp, pK_a, D, and S₀^LLPS), except for PAP-HCl.