Adelle Altnurme's bachelor's thesis was awarded 1st prize in the field of natural sciences at the 2024 national student research paper competition. Supervisors Mare Oja and Uko Maran received a letter of appreciation for their supervision.
Uko Maran
Adelle Altnurme's bachelor's thesis, "Experimental determination of octanol-water distribution coefficients of poorly soluble drug substances and comparison with predicted values", was awarded the 1st prize in the 2024 national student research competition in the field of natural sciences, for students category of applied higher education and bachelor's studies (with a prize money of 1700 euros, education and research minister decree of 10.12.2024 No. 1.1-2/24/330). Mare Oja and Uko Maran, received a letter of appreciation for supervising the research.
Problem statement and brief summary of the awarded research:
In the early stages of drug development, where suitable lead compounds are sought, the main properties to be investigated are the absorption, transport and binding of chemical compounds to the active site of the protein. There is a trend that virtual and high-throughput screening of chemical compounds prefers more hydrophobic and less soluble compounds as lead compound candidates. For example, an estimated 40% of currently used drug substances and almost 90% of drug substance candidates in development have low solubility, which makes the study of compounds with such properties, so-called poorly soluble compounds, particularly important. Dissociation must certainly be considered in the case of such compounds, since approximately 64% of drug substances are dissociable compounds, the chemical properties of which depend largely on the pH of the environment.
The hydrophobic/hydrophilic properties of drug substances are typically characterized by the partition coefficient (logPN), which describes the distribution of an uncharged chemical compound between two phases, for which the octanol-water system is commonly used. So far, the use of the partition coefficient has largely ignored the fact that a large number of chemicals and drug substances dissociate in the human body and in the environment depending on pH. For example, there are highly acidic and basic regions in the gastrointestinal tract, which affect the hydrophobic/hydrophilic properties of drug substances and thus also the absorption of drug substances. In such a situation, where the drug substance is mainly present in a dissociated form, it is practical to use the distribution coefficient (logD), which also describes the distribution between two phases, but takes into account the ratio of charged to uncharged forms of the compounds, to characterize the hydrophobic/hydrophilic properties. At present, there is no systematic experimental approach to the logD values of poorly soluble compounds over a wide pH range, which was the focus of Adelle's research.
In drug development and toxicology, predictive methods are widely used to estimate partition coefficient and distribution coefficient values. This raised the research question of how well the distribution coefficient values of poorly soluble compounds predicted by predictive methods agree with experimental values. In this work, the octanol-water distribution coefficients of 35 poorly soluble drug substances were experimentally determined at pH values of 3, 5, 7.4 and 9 and compared with the values predicted by four software. The important novelty of the study was that the experimental pH-logD profiles of poorly soluble drug substances, which are currently absent in the open literature, were thoroughly investigated and compared with the predicted pH-logD profiles. As a result of the study, it was explained what problems occur in predicting the pH-logD profiles of poorly soluble drug substances. The existence of this type of systematic information is also necessary for the development of new predictive methods that would allow for more accurate estimation of the logD values of compounds in a wide pH range.
