Quantitative Solubility Relationships and the Effect of Water Uptake in Triglyceride/Monoglyceride Microemulsions

• Published in: Pharmaceutical research Vol. 25; no. 5; pp. 1158 - 1174
• Main Authors: Rane, Sagar S., Cao, Yichen, Anderson, Bradley D.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.05.2008; Springer; Springer Nature B.V
• Subjects: Algorithms; Biochemistry; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedical research; Biomedicine; Caprylates - chemistry; Chemical Phenomena; Chemistry, Physical; Chromatography, High Pressure Liquid; Emulsions; Excipients - chemistry; General pharmacology; Humidity; Hydrogen Bonding; Hydrogen bonds; Indicators and Reagents; Medical Law; Medical sciences; Models, Molecular; Monoglycerides - chemistry; Oils; Pharmaceutical technology. Pharmaceutical industry; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Regression Analysis; Research Paper; Solubility; Solvents; Triglycerides - chemistry; Water - analysis; lipid formulation; solubility; microemulsions; triglycerides/monoglycerides; linear free energy relationships; Water; Pharmaceutical technology; Solubility; Lipids; Triglyceride; Uptake; Monoglyceride; Formulation; Microemulsion; Physicochemical properties; Quantitative analysis
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-007-9500-4

Purpose This paper aims to elucidate quantitative relationships between small molecule solubility/water-uptake in triglyceride/monoglyceride lipid formulations, the chemical structure of the solute, and the solvent composition. Methods Solubility and water uptake in tricaprylin/1-monocaprylin and tricaprylin/1-monocaprin mixtures in the “microemulsion” region at 37°C were determined with HPLC and KF coulometry, respectively. Twelve model solutes varying in hydrogen bond acidity, basicity, polarity, and molecular volume were chosen. Linear free energy relationships (LFER) (Abraham type) were implemented to obtain solvent coefficients at various monoglyceride concentrations. Results Profiles for both solubility and water uptake (at different water activities) in lipid mixtures containing different monoglycerides were superimposable, producing a single master curve when the monoglyceride concentrations were plotted on a molar scale. The LFER derived solvent coefficients showed a systematic dependence on the lipid composition consistent with the view that relative solubility is determined largely by the molar concentrations of individual functional groups such as glyceride ester moieties and hydroxyl groups. At low RH, water uptake increased linearly with monoglyceride concentration while cooperativity was evident in water uptake profiles at high RH. Conclusions This study provides a potential universal framework for predicting relative drug solubility in mixtures containing fully saturated triglycerides and monoglycerides.