Influence of Electrolytes, pH, and Alcohol Concentration on the Solubilities of Acidic Drugs†‡

Phosphate Precipitates and Water-Soluble Aggregates in Re-analyzed Solubility-pH Data of Twenty-five Basic Drugs

“…There are numerous reports of aggregation forming systems [1,[5][6][7][8][9][10][11][12]. For example, doxycycline [8], with intrinsic solubility S 0 0.72 mg•mL -1 , at 25 °C in 1 M NaCl/HCl acidic solutions, forms dimers with K 2 = 24 M -1 .…”

“…The reported CMC of diclofenac is about 25 mM and of ketoprofen is about 160 mM [10]. The re-analysis of the data of Higuchi et al [7] indicated that barbital and phenobarbital likely formed anionic dimers (reaching peak concentrations near pH 8), whereas oxytetracycline showed a pronounced tendency to form a cationic dimer (peaking near pH 2) [11]. Saturated alkaline solutions of diprenorphine (pH > 9) appeared to suggest the formation of a mixedcharge anionic dimer [12].…”

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

“…There are only a handful of other examples of sub-micellar aggregation (Higuchi et al, 1953;Bogardus and Blackwood, 1979;Serajuddin and Rosoff, 1984;Serajuddin and Jarowski, 1985;Fini et al, 1995;Zhu and Streng, 1996;Ledwidge and Corrigan, 1998;Jinno et al, 2000). In the above examples, the stoichiometries of aggregation were estimated from the re-analysis of published solubility-pH data (Avdeef 2007(Avdeef , 2012; Völgyi et al, 2013;Avdeef, 2014a,b;Butcher et al, 2015).…”

Salt Solubility Products of Diprenorphine Hydrochloride, Codeine and Lidocaine Hydrochlorides and Phosphates – Novel Method of Data Analysis Not Dependent on Explicit Solubility Equations

“…All these effects can complicate the interpretation of the solubility data [9][10][11][12][13][14][15][16][17][18]. Such complexity may not be evident unless a full solubility -pH profile is measured, over a pH range containing the uncharged and charged forms of the drug, preferably at more than one solid-sample excess.…”

“…For this reason, salt solubility analysis of data in the past had been done on a case by case basis, sometimes using incomplete explicit solubility equations. At times the impact of aggregation reactions had been recognized but not dealt with quantitatively, presumably because computational methods were not available at the time [9,10,16].…”