Revisiting the solubility concept of pharmaceutical compounds

The kinetic and thermodynamic solubilities of Roche (Ro) pharmaceutical com pounds were determined by HPLC, titrimetry, and UV/Vis spectroscopy in aque ous buffers and in nonbuffered systems. For kinetic solubility, a turbidime tric method that allows the rapid determination of solubilities using small amounts of compounds (5-50 mg) was used. Two types of precipitation were o bserved during the kinetic solubility determinations: i) a disperse precipi tation where the solution became foggy with very small particles uniformly distributed in the solution, and ii) discrete precipitation characterized b y fort-nation of crystals that rapidly sediment. The thermodynamic solubili ty was determined by shake flask and titrimetrically using a pH-STAT. The p H-STAT titrimetric method for the pH-thermodynamic solubility profile deter mination eliminates the buffer species and represents a new way to approach the solubility characterization of pharmaceutical compounds. The strengths of the turbidimetric method for determining the kinetic solubility are its rapidity, minimal compound requirements, and suitability for high throughp ut screening. The limitations are that the maximum solubility is limited to less than 100 mg . cm(-3), and the precipitation of trace impurities canno t be distinguished from precipitation of the analyte. The pH-STAT titrimetr ic approach for the thermodynamic solubility has a lower throughput and is suitable for the characterization of the lead candidate. It is not limited in its solubility range and provides a common basis for the comparison of t he solubility values at different pH values in contrast to traditional buff ered systems.