title: Phenothiazines solution complexity - Determination of pKa and solubility-pH profiles exhibiting sub-micellar aggregation at 25 and 37°C.
abstract: The ionization constants (pKa) and the pH-dependent solubility (log S-pH) of six phenothiazine derivatives (promazine hydrochloride, chlorpromazine hydrochloride, triflupromazine hydrochloride, fluphenazine dihydrochloride, perphenazine free base, and trifluoperazine dihydrochloride) were determined at 25 and 37°C. The pKa values of these low-soluble surface active molecules were determined by the cosolvent method (n-propanol/water at 37°C and methanol/water at 25°C). The log S-pH profiles were measured at 24h incubation time in 0.15M phosphate buffers. The log S-pH "shape-template" method, which critically depends on accurate pKa values (determined independently of solubility data), was used to propose speciation models, which were subsequently refined by rigorous mass-action weighted regression procedure described recently. Differential scanning calorimetry (DSC), UV-visible spectrophotometry, potentiometric, and high performance liquid chromatography (HPLC) measurements were used to characterize the compounds. The intrinsic solubility (S0) values of the three least-soluble drugs (chlorpromazine·HCl, triflupromazine·HCl, and trifluoperazine·2HCl) at 25°C were 0.5, 1.1, and 2.7μg/mL (resp.). These values increased to 5.5, 9.2, and 8.7μg/mL (resp.) at the physiological temperature. The enthalpies of solution for the latter compounds were exceptionally high positive (endothermic) values (99-152kJ·mol(-1)). Cationic sub-micellar aggregates were evident (from the distortions in the log S-pH profiles) for chlorpromazine, fluphenazine, perphenazine, and trifluoperazine at 25°C. The effects persisted at 37°C for chlorpromazine and trifluoperazine. The solids in suspension were apparently amorphous in cases where the drugs were introduced as the chloride salts.
authors.affiliation: Department of Physical Chemistry, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland. Electronic address: pobudka@ch.pw.edu.pl.
authors.forename: Aneta
authors.initials: A
authors.lastname: Pobudkowska
authors.affiliation: Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Ràfols
authors.affiliation: Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Subirats
authors.affiliation: Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bosch
authors.affiliation: in-ADME Research, 1732 First Avenue #102, New York, NY 10128, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Avdeef
mesh_terms: D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D006863:Hydrogen-Ion Concentration; D008823:Micelles; D010640:Phenothiazines / Q000008:administration & dosage*; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013696:Temperature
chemical_list: D008823:Micelles; D010640:Phenothiazines
keywords: Cosolvent pK(a); Henderson-Hesselbalch relationships; Shake-flask method; Solubility-pH; Surface-active drugs