This is the first blog of a long series of personal perspectives on scientific articles and events related to Analytical Chemistry.
In September 2019, PIC Analytics co-organized a workshop on Physicochemical Properties with Analiza. Analiza is a Physicochemical and ADME Property Screening Services company that proposes analytical services on major Physicochemical Properties, such as lipophilicity and solubility, and our long working relationship led us to propose a scientific forum to expose some strategies on the use of Physicochemical Properties towards the design of successful New Chemical Entities (Presentation of Franco Lombardo) and to present some new techniques and tools for new Descriptors (Sarah St John with the classification of chromatographic columns to highlight interactions and Simone Sciabola on the EPSA model). We have also learned about Chameleonic Index from Giulia Caron on “Beyond Rule of 5” compounds, and on “Polarity Index” with Gilles Goetz on the EPSA technique by SFC.
During specific sessions, attendees had the opportunity to network and share about design strategies and future needs.
Overall it was a success for this first workshop because it has created the opportunity to build a good foundation towards deeper knowledge on the development of Physicochemical Properties to support successful design and development of clinical candidates.
The feedback received on this workshop highlights the needs for training, study-cases, and innovation. In the next few years I will therefore focus on providing an intensive customized on-line and face-to-face training program, informing about successful and less successful compounds development based on available data, and promoting novelty whether it is about new chemical space, such as “Beyond Rule of 5”, potential new physicochemical descriptors, or new tools and techniques.
Speaking about novel techniques, EPSA (that could be considered as a Polarity Index) has been developed by SFC to mimic interactions of a compound with a membrane-like environment and highlights the exposed polarity of molecules in contact to a membrane, indirectly pointing to the presence of Intra Molecular Hydrogen Bond (IMHB) and emphasizing molecule flexibility (1). It has been shown that for some cyclic peptides, EPSA index is directly connected to permeability and can therefore be used as permeability predictor (2).
Logk’PLRPS is another technique that offers different potentials of highlighting lipophilicity in an “aprotic” environment as well as the presence of ionized species at a given pH whether they are acids or bases(3). This is a qualitative method based on the measurement of retention time of ionized species that is shorter than the neutral ones. The retention time indeed decreases when the amounts of ionized species increase at different pHs and remains constant in the presence of a majority of neutral entities. This retention can mainly be explained by the large size of the ionized species that are less retained in the network of the Polystyrene divinyl-benzene of the stationary phase, compared to the corresponding neutral forms that are of smaller size. As an unexpected outcome, this leads to highlight the presence of zwitterions within the distributions of species according to the pH.
Now this raises the 2 main questions:
- Could the Logk’PLRPS technique be quantitative like any other chromatographic technique to evaluate the amounts of ionized species versus neutral form of a molecule at different pHs, by calculating the ratio of peak area?
- Could we envision a direct relationship between these peak area ratio (associated to their respective retention times on PLRPS stationary phase) and the permeability of a compound at different ionization stages (i.e. at different pHs)? The resulting profile of ratio ionized species/neutral form against permeability would provide a permeability “shape” and would help understand the impact of ionized species on permeability and provide additional tools for the design of new chemical entities. Such an experiment would also probably help optimize and further use the PLRPS chromatographic technique as a quick way to predict a “probability for permeability” or a “Permeability Index”.
In addition, it has been shown that the PLRPS technique can also provide information on potential IMHB formation in neutral species, characterized by the decrease of their retention time due to smaller size (the IMHB tends to “shrink the molecule”). How about IMHB presence in ionized species? Will the PLRPS technique be sensitive enough to show a decrease in retention time due to a size reduction induced by an IMHB? This would first require to select compounds that have IMHB at different ionization stages, such as the protonated sildenafil(4) . Then we would need to correlate the PLRPS retention times with the EPSA index, the permeability, and the lipophilicity, and it could become very complex.
That being said, I strongly believe that the PLPRS chromatographic technique can provide important information on the ionization of species and can help mimic compound conformation in different environments.
(1) “High Throughput Method for the Indirect Detection of Intramolecular Hydrogen Bonding”, G.H. Goetz, W. Farrell, M. Shalaeva, S. Sciabola, D. Anderson, J. Yan, L. Philippe, M. J. Shapiro, J. Med. Chem, 2014, 57, 2920-2929,
(2) “EPSA: A Novel Supercritical Fluid Chromatography Technique Enabling the Design of Permeable Cyclic Peptides”, G. H. Goetz, L. Philippe, M. J. Shapiro, ACS Med Chem Letters 2014, 5, 1167-1172,
(3) “A Fast Chromatographic Method for Estimating Lipophilicity and Ionization in Nonpolar Membrane-Like Environment”, G. Caron, M. Vallaro, G. Ermondi, G. Goetz, Y. Abramov, L. Philippe, M. Shalaeva, Molecular Pharmaceutics, publication on line January 2016,
(4) “Physicochemical Characterization of Sildenafil: Ionization, LipophilicityBehavior, and Ionic-Partition Diagram Studied by Two-Phase Titration and Electrochemistry”, V. Gobry, G. Bouchard, P.A. Carrupt , B. Testa, H. H. Girault, Helvetica Chemica Acta, 2000, (83), 1465-1473.