Phenothiazines solution complexity – Determination of pKa and solubility-pH profiles exhibiting sub-micellar aggregation at 25 and 37 °C

Aneta Pobudkowska-Mirecka , Rafols Clara , Subirats Xavier , Bosch Elisabeth , Avdeef Alex


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 24 h incubation time in 0.15 M 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 2.7 μg/mL (resp.). These values increased to 5.5, 9.2, and 8.7 μg/mL (resp.) at the physiological temperature. The enthalpies of solution for the latter compounds were exceptionally high positive (endothermic) values (99–152 kJ·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.
Author Aneta Pobudkowska-Mirecka (FC / DPC)
Aneta Pobudkowska-Mirecka,,
- Department Of Physical Chemistry
, Rafols Clara
Rafols Clara,,
, Subirats Xavier
Subirats Xavier,,
, Bosch Elisabeth
Bosch Elisabeth,,
, Avdeef Alex
Avdeef Alex,,
Journal seriesEuropean Journal of Pharmaceutical Sciences, ISSN 0928-0987
Issue year2016
Publication size in sheets0.65
Keywords in EnglishSolubility-pH; Cosolvent pKa; Surface-active drugs; Shake-flask method; Henderson-Hesselbalch relationships
ASJC Classification3003 Pharmaceutical Science
Languageen angielski
1-s2.0-S0928098716302676-main.pdf 2.15 MB
Score (nominal)35
Score sourcejournalList
ScoreMinisterial score = 35.0, 31-01-2020, ArticleFromJournal
Ministerial score (2013-2016) = 35.0, 31-01-2020, ArticleFromJournal
Publication indicators Scopus Citations = 8; Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.52; WoS Impact Factor: 2016 = 3.756 (2) - 2016=3.866 (5)
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