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 () exceeds the intrinsic LLPS concentration () 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 pH and values at pHs 4.0-9.5 (citric acid, phosphoric acid, and boric acid, buffer capacity = ca. 4 mM/ΔpH) were calculated using the , solubility product (), and diffusion coefficient () of a drug. was measured using the pH-shift method. UWL-LLPS was predicted to occur when ≥ . The prediction result was then compared with UWL-LLPS observed at each pH by polarized light microscopy (PLM). The pH-LLPS concentration () 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 was close to . Furthermore, UWL-LLPS was not accurately predicted in the case of PAP-HCl. The pH- 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 (, , , and ), except for PAP-HCl.