title: Spectrophotometric pKa determination of ionizable pharmaceuticals: Resolution of molecules with weak pH-dependent spectral shift.
abstract: The extent of ionization of a drug molecule at different pH values can be characterized by its pKa (acid dissociation constants). It is an important parameter in pharmaceutical development to rationalize the physiochemical and biopharmaceutical properties of the drug molecule. UV titration for pKa determination is one of the popular methods. The success of this method requires the molecule exhibiting strong pH-dependent spectral shift related to the ionization process. Depending on the proximity between the ionizable group and the chromophore, the spectral shift may not be strong enough to warrant a successful determination. In a previous study, it has been reported that a distance of three σ bonds between the chromophore and the ionizable group was the limit for a precise pKa determination. In this work, a UV titration method for pKa determination, with a particular emphasis on molecules with weak pH-dependent spectral shift is investigated. It has been shown that the pKa values determined from this study are in good agreement with those determined using potentiometric method and literature data (R(2)=0.998). Our methodology revealed that successful pKa determination is feasible even with a separation distance of five σ bonds between the chromophore and the ionizable group.
authors.affiliation: Pion Inc., 10 Cook Street, Billerica, MA 01821, USA.
authors.forename: Deren
authors.initials: D
authors.lastname: Dohoda
authors.affiliation: Pion Inc., 10 Cook Street, Billerica, MA 01821, USA.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Tsinman
authors.affiliation: Pion Inc., 10 Cook Street, Billerica, MA 01821, USA.
authors.forename: Oksana
authors.initials: O
authors.lastname: Tsinman
authors.affiliation: Pion Inc., 10 Cook Street, Billerica, MA 01821, USA.
authors.forename: Haotian
authors.initials: H
authors.lastname: Wang
authors.affiliation: Drug Development Core, Faculty of Health Sciences, University of Macau, Macau, China. Electronic address: kintam@umac.mo.
authors.forename: Kin Y
authors.initials: KY
authors.lastname: Tam
mesh_terms: D001702:Biopharmaceutics; D006863:Hydrogen-Ion Concentration; D007477:Ions; D016018:Least-Squares Analysis; D008027:Light; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011199:Potentiometry; D011433:Propranolol / Q000032:analysis; D015203:Reproducibility of Results; D013053:Spectrophotometry / Q000379:methods*; D013696:Temperature; D014640:Vancomycin / Q000032:analysis
chemical_list: D007477:Ions; D004364:Pharmaceutical Preparations; D014640:Vancomycin; D011433:Propranolol
keywords: Alternating least square analysis; Ionization; Physiochemical property; UV absorption spectroscopy; pK(a)