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The acid-base chemistry of a tetraprotic, ampholyte ACE inhibitor, lisinopril, was studied by different methods. Potentiometry in aqueous medium and a co-solvent technique in methanol-water mixtures as well as 1H NMR-pH titration were applied for the highly precise measurement of protonation macroconstants. The log K values of lisinopril (at 25.0°C and 0.15 M ionic strength) were found: log K1 = 10.75 ± 0.01, log K2 = 7.13 ± 0.01, log K3 = 3.13 ± 0.01, log K4 = 1.63 ± 0.01, calculated as an average of the best two values obtained by independent methods. NMR-pH titration was used to assign the constants to the functional groups and for the examination of site-specific, submolecular basicities of the molecule (determination of protonation microconstants). In the first two well-separated protonation steps, the macro- and microconstants were identical and assigned to the primary amino group (log K1 = log kA) and to the secondary amine basicity (log K2 = log kBA), respectively. The two carboxylates exhibited overlapping protonation characterised first by microconstants (log = 2.15 log = 3.10), revealing that the carboxylate on the proline ring has nine times greater intrinsic basicity than the carboxylate on the side chain. The distribution of protonation species (Lis2-; HLis-; H2Lis; H3Lis+; H4Lis2+) and microspecies (ABC; ABD) as a function of pH was calculated and used to interpret the pharmacokinetic and pharmacodynamic properties of lisinopril.

A novel general approach was described to address many of the challenges of salt solubility determination of drug substances, with data processing and refinement of equilibrium constants encoded in the computer program pDISOL-XTM. The new approach was illustrated by the determinations of the solubility products of diprenorphine hydrochloride, codeine hydrochloride and phosphate, lidocaine hydrochloride and phosphate at 25 oC, using a recently-optimized saturation shake-flask protocol. The effects of different buffers (Britton-Robinson universal and Sörensen phosphate) were compared. Lidocaine precipitates were characterized by X-ray powder diffraction (XRPD) and polarization light microscopy. The ionic strength in the studied systems ranged from 0.25 to 4.3 M. Codeine (and possibly diprenorphine) chloride were less soluble than the phosphates for pH > 2. The reverse trend was evident with lidocaine. Diprenorphine saturated solutions showed departure from the predictions of the Henderson-Hasselbalch equation in alkaline (pH > 9) solutions, consistent with the formation of a mixed-charge anionic dimer.