Effects of surface active characteristics and solid state forms on the pH solubility profiles of drug–salt systems

Abstract The pH solubility profiles of five drug–salt systems (diclofenac sodium, diclofenac N -(2-hydroxyethyl)pyrrolidine, CEL50 phosphate, theophylline sodium and phenazopyridine hydrochloride) were examined. With the exception of the diclofenac sodium (Na) system supersaturation was observed at the theoretical pH of maximum solubility (pH max ) in all profiles. Characterisation of the solid phases involved indicated that inhibition of nucleation of the final solid form is responsible for the formation of supersaturated solutions at the pH max . The surface active characteristics of the drug–salts were investigated and a general relationship between supersaturation at the pH max and self-association of the drug–salts was observed. It is proposed that self-association of the drug in the region of the pH max reduces the rate of nucleation of the final salt. Furthermore higher levels of supersaturation are observed when the free drug is used as the starting material indicating the key role of the solid phase employed in determining the level of supersaturation obtained. Possible pharmaceutical applications of supersaturation at the pH max are discussed.