(M1030-12-71) Equilibrium Solubility and Solute-Solvent Interactions of Four Drugs in Mono-Solvents

Purpose: The present study was conducted to measure the solubility of each drug in various mono-solvents and determined the solvent effect using the KAT-LSER model for use in the preformulation and formulation development stages.

Methods: The solid-liquid (S-L) equilibrium by using the shake-flask technique was used to measure the solubility of each drug in various mono-solvents was measured at temperatures ranging from 288.15 K to 308.15 K under atmospheric pressure. The concentration of drug was determined by HPLC-UV. The thermal characteristics and crystalline form of drug was analyzed by differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD), respectively. To understand the solvent effect (solvation interaction) on the solubility of each drug, the KAT-LSER model was applied to fit and correlate the experimental solubility data.

Results: All drugs have positive correlation between solubility and temperature. The mole fraction solubility of oxcarbazepine, bisacodyl, carvedilol, rebamipide was highest in NMP, NMP, PEG 400 and PEG 400, respectively. Oxcarbazepine has positive correlations of α and π*, which means that hydrogen bond acidity and nonspecific dipolarity/polarizability of solvent resulted in the increased solubility of drug. In contrast, the solubility decreased as the self-cohesiveness of the solvent increased. Bisacodyl and carvedilol have positive correlation of β and δ_H, which means that the solubility increases with increasing hydrogen bond basicity and self-cohesiveness of the solvent. While the solubility decreased as the hydrogen bond acidity of the solvent increased. Rebamipide has positive correlation of β and π*, which means that solubility is increased with increasing hydrogen bond basicity and non-specific dipolarity/polarizability of the solvent. It was difficult to explain solubility profiles of oxcarbazepine and bisacodyl using a single parameter because they have no clear relationship with physical properties of solvent, such as the polarity index, dipole moment, dielectric constant. PEG 400 has a low dielectric constant/polarity with results in strong solute-solvent interactions with carvedilol and rebamipide which owing to hydrogen bond donor/acceptor.>

Conclusion: The experimental solubility data of each drug in various mono-solvents was determined at 288.15-308.15 K by using S-L equilibrium. In addition, the KAT-LSER model was applied to analyze the solvent effect on the solubility of each drug at 298.15 K. Based on KAT-LSER model analysis, both dipolarity-polarizability (π*) and cohesive energy density (δ_H) were most important effect on solubility of oxcarbazepine. Hydrogen bond acidity (α) and cohesive energy density (δ_H) appeared to contribute more than other solvent effect on solubility of bisacodyl. Hydrogen bond acidity (α) had the most excellent effect on solubility of carvedilol. For rebamipide, hydrogen bonding interaction (α and β) and dipolarity/polarizability (π*) for the solute-solvent pairing are the same for the solubility. These findings can help to understand how the types of solvent affect the solvation of drug, and to find effective solvents for improved solubility of poorly soluble drugs. In addition, the experimental and calculated solubility results of drugs in various mono-solvents can be utilized in drug development, such as solubilization techniques to increase the bioavailability.

Acknowledgments: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1A2C4002166).