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

被引:3
作者
Uekusa, Taiga [1 ]
Sugano, Kiyohiko [1 ]
机构
[1] Ritsumeikan Univ, Coll Pharmaceut Sci, Mol Pharmaceut Lab, Kusatsu, Shiga 5258577, Japan
关键词
liquid-liquid phase separation; salt formulation; supersaturation; solid surface pH; oral absorptionmodeling; PH-SOLUBILITY PROFILES; DIFFUSION LAYER PH; SUPERSATURATED SOLUTIONS; HYDROCHLORIDE SALTS; DISSOLUTION RATE; CARBOXYLIC-ACIDS; KINETICS; DELIVERY; BEHAVIOR; BASES;
D O I
10.1021/acs.molpharmaceut.3c00157
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
During the dissolution of drug salt particles, liquidliquid 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 (S0LLPS) 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 (PRFHCl) 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/.pH) were calculated using the pKa, solubility product (Ksp), and diffusion coefficient (D) of a drug. S0LLPS was measured using the pH-shift method. UWL-LLPS was predicted to occur when C0 = S0LLPS. The prediction result was then compared with UWL-LLPS observed at each pH by polarized light microscopy (PLM). The pH-LLPS concentration (SpHLLPS) 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 S0LLPS. Furthermore, UWL-LLPS was not accurately predicted in the case of PAP-HCl. The pH-SpHLLPS 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 (Ksp, pKa, D, and S0LLPS), except for PAPHCl.
引用
收藏
页码:3140 / 3149
页数:10
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