| Autor: |
Uekusa T; Molecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higashi, Kusatsu, Shiga 525-8577, Japan., Sugano K; Molecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higashi, Kusatsu, Shiga 525-8577, Japan. |
| Jazyk: |
angličtina |
| Zdroj: |
Molecular pharmaceutics [Mol Pharm] 2023 Jun 05; Vol. 20 (6), pp. 3140-3149. Date of Electronic Publication: 2023 May 14. |
| DOI: |
10.1021/acs.molpharmaceut.3c00157 |
| Abstrakt: |
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 ( C 0 ) exceeds the intrinsic LLPS concentration ( S 0 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 pH 0 and C 0 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. S 0 LLPS was measured using the pH-shift method. UWL-LLPS was predicted to occur when C 0 ≥ S 0 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 C 0 was close to S 0 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 S 0 LLPS ), except for PAP-HCl. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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