Solubility of E2050 at various pH: a case in which apparent solubility is affected by the amount of excess solid.
The solubility of E2050, supplied as a dihydrochloride salt, in aqueous solutions at different pHs was studied. Two pK(a)s controlling the equilibrium between the various protonated species were determined. The solubility-pH profile of E2050 is expected to be high in acidic solutions because protonated species are formed and to be low in alkaline conditions due to the formation of hydrophobic free base. The solubility is also affected by chloride ion, a common ion for this drug substance. Two solubility products (K(sp)) were determined corresponding to the solubility of di-HCl salt and mono-HCl salt. Based on the pK(a)s (3.10 and 7.71), the solubility products with chloride (2.92 and 3.77 as corresponding pK(sp)), and the solubility of free base (2 x 10(-5) M), the solubility in solutions with different pH and different levels of chloride ion can be predicted. The prediction of the solubility change during the dilution of E2050 parenteral formulations by saline was also demonstrated. Furthermore, the present study presents an interesting example in which an apparent solubility can be different if varying (excess) amounts of salt are added to the solution. In this case, excess chloride ion suppresses the solubility in the pH region where mono-HCl salt controls the solubility.
Wang
Zeren
Z
Eisai Inc., Research Triangle Park, North Carolina 27709, USA. zeren.wang@pharma.novartis.com
Burrell
Lana S
LS
Lambert
William J
WJ
D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002712:Chlorides / Q000737:chemistry; D006851:Hydrochloric Acid / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D010879:Piperazines / Q000737:chemistry*; D012995:Solubility
D002712:Chlorides; C466038:E2050; D010879:Piperazines; D006851:Hydrochloric Acid