Solubility of poorly soluble compounds in excipients of lipid-based
formulations
Linda C. Persson1*, Christopher J. Porter2, William N. Charman2, Christel A.S. Bergström1
1
Department of Pharmacy, Uppsala University, Sweden
MIPS, Monash University, Melbourne Australia
2
Introduction
At present between 40-70% of all new chemical entities are of poor aqueous solubility when
entering the drug development process.1 The demand for enabling formulations such as
lipid-based formulations (LBFs) has therefore increased since these may facilitate drug
absorption.2 Optimization of these formulations is a complex task and currently performed
experimentally.
Aim
To investigate solubility of poorly water soluble drugs in excipients of LBFs. Further to use
the obtained solubility data to develop computational tools for formulation selection.
Method
A series of 30 structurally diverse lipophilic compounds (logP of 2.7-6.6) was measured for
solubility in soybean oil (SBO), captex 355, polysorbate 80 (PS80) and polyethylene glycol
400 (PEG400) at 37°C by the shake-flask method coupled to HPLC-UV analysis. Obtained data
was used to investigate correlations of solubility and physiochemical properties.
Results
The solubility ranged from <0.01 mg/g (SBO) to >300 mg/g (PEG400). SBO and Captex
showed equal solvation capacity (Fig 1a). Unexpectedly, the correlation between solvation
capacity of PS80 and PEG400 also proved to be strong (Fig 1b). Computed data revealed
correlation between lipid solubility and melting point, whereas no correlation with logP was
established. This indicates that lipid solubility is highly dependent on solid state properties, a
dependency that was not found important for PS80 and PEG400 solubility.
b)
0
logS CAPTEX355  1.04  logS SBO  0.15
logSPEG400(mol/mol)
logSCaptex355 (mol/mol)
a)
R 2  0.98
-2
-4
-6
0
Fig. 1. Solubility correlations
between different excipients;
a) glycerides and b) ethoxylated
excipients.
logS PEG400  0.95  logS PS80  0.51
R  0.85
2
-1
-2
-3
-4
-6
-5
-4
-3
logS SBO(mol/mol)
-2
-1
-4
-3
-2
-1
0
logSPS80(mol/mol)
Conclusion
A solubility database suitable for modeling solubility in common pharmaceutical excipients
was established and molecular properties of importance for lipid solubility were identified.
References
1. Rane S. S. et al. Adv Drug Deliv Rev (2008) 60: 638-656
2. Porter C. J. H. et al. Nature Rev (2007) 6: 231-248