Estimation of the octanol-water distribution coefficient of basic compounds by a cationic microemulsion electrokinetic chromatography system

Abstract

<jats:p>&lt;p class="ADMETabstracttext"&gt;The octanol-water partition coefficient (P&lt;sub&gt;o/w&lt;/sub&gt;), or the octanol-water distribution coefficient (D&lt;sub&gt;o/w&lt;/sub&gt;) for ionized compounds, is a key parameter in the drug development process. In a previous work, this parameter was estimated through the retention factor measurements in a sodium dodecyl sulfate (SDS) - microemulsion electrokinetic chromatography (MEEKC) system for acidic compounds. Nonetheless, when ionized basic compounds were analyzed, undesirable ion pairs were formed with the anionic surfactant and avoided a good estimation of log D&lt;sub&gt;o/w&lt;/sub&gt;. For this reason, an alternative MEEKC system based on a cationic surfactant has been evaluated to estimate P&lt;sub&gt;o/w&lt;/sub&gt; or D&lt;sub&gt;o/w&lt;/sub&gt; of neutral compounds and ionized bases. To this end, it has been characterized through the solvation parameter model (SPM) and compared to the octanol-water partition system. Results pointed out that both systems show a similar partition behavior. Hence, the log P&lt;sub&gt;o/w&lt;/sub&gt; of a set of neutral compounds has been successfully correlated against the logarithm of the retention factor (log k) determined in this MEEKC system. Then, the log D&lt;sub&gt;o/w&lt;/sub&gt; of 6 model bases have been estimated at different pH values and they have been compared to data from the literature, determined by the reference shake-flask and potentiometric methods. Good agreement has been observed between the literature and the estimated values when the base is neutral or partially ionized (up to 99 % of ionization).&lt;/p&gt;</jats:p>

Comparison of the retention of basic compounds in anionic and cationic microemulsion electrokinetic chromatographic systems

“…of the two ME systems has been correlated to two structural descriptors that may have an important influence on their retention: the McGowan volume and the log Po/w. On one hand, it has been demonstrated that the McGowan volume has a very important contribution when the retention of neutral compounds is evaluated in MEEKC systems.On the other hand, good correlations have been observed between log Po/w and the retention of neutral compounds in these two MEEKC systems[6,25]. Correlations are shown in FiguresS2a and S2bof the supplementary information.…”

“…The use of basic or acidic compounds to prepare the buffers does not affect the mobilities obtained, indicating that aggregation of protonated bases is mainly caused by the SDS surfactant. a) Data from [24]; b) Data from [25]; c) Measured in this work.…”

“…10 and Figure 1A (data obtained from [16,17]), where it is seen that the it is not very good. In MEEKC, the retention of neutral compounds in the two equivalent systems considered (indicated by SDS-MEEKC and TTAB-MEEKC subscripts) has been also compared using data previously determined [24,25] and data measured in this work (Table 1). The results are presented in Eq.…”

“…These bases must have pKa values between 5 and 10 so that the entire profile can be determined, and must be easily detectable by UV-vis. We have selected compounds of different lipophilicity to assure different levels of interaction with the microemulsions, since the retention factor of the unionized forms of the compounds presents a good correlation with the octanol-water partition coefficient (log Po/w), commonly used to estimate lipophilicity [25]. The physicochemical properties (log Po/w,…”

Prediction of hERG inhibition of drug discovery compounds using biomimetic HPLC measurements

“…Certain physicochemical properties of molecules have been recognized as early indicators of potential problems with early drug discovery compounds [ 19 ]. Besides lipophilicity [ 20 ], solubility [ 21 ] and permeability, biomimetic properties such as protein [ 22 ] and phospholipid binding [ 23 ] can be measured at the early stages of the drug discovery process [ 24 ]. The chromatographic technique provides an automated, high throughput and reliable measurement of important properties of the drug discovery compounds [ 25 ] that can be used to estimate later stage in vivo properties of compounds such as the volume of distribution, the unbound volume of distribution [ 26 ] and the drug efficiency [ 27 ].…”