Novel medium-throughput technique for investigating drug-cyclodextrin complexation by pH-metric titration using the partition coefficient method
The present study was aimed to develop a medium-throughput screening technique for investigation of cyclodextrin (CD)–active pharmaceutical ingredient (API) complexes. Dual-phase potentiometric lipophilicity measurement, as gold standard technique, was combined with the partition coefficient method (plotting the reciprocal of partition coefficients of APIs as a function of CD concentration). A general equation was derived for determination of stability constants of 1:1 CD–API complexes (K1:1,CD) based on solely the changes of partition coefficients (log log P P o/w− N appN ), without measurement of the actual API concentrations. Experimentally determined logP value (−1.64) of 6-deoxy-6[(5/6)-fluoresceinylthioureido]-HPBCD (FITC-NH-HPBCD) was used to estimate the logP value (≈ −2.5 to −3) of (2-hydroxypropyl)-ß-cyclodextrin (HPBCD). The results suggested that the amount of HPBCD can be considered to be inconsequential in the octanol phase. The decrease of octanol volume due to the octanol–CD complexation was considered, thus a corrected octanol–water phase ratio was also in- troduced. The K1:1,CD values obtained by this developed method showed a good accordance with the results from other orthogonal methods.