Toward an In Vivo Dissolution Methodology: A Comparison of Phosphate and Bicarbonate Buffers

The purpose of this research was to evaluate the difference between the pharmaceutical phosphate buffers and the gastrointestinal bicarbonates in dissolution of ketoprofen and indomethacin, to illustrate the dependence of buffer differential on biopharmaceutical properties or BCS II weak acids, and to recommend phosphate buffers equivalent to bicarbonates. The intrinsic dissolution rats of ketoprofen and indomethacin ware experimentally measured using a rotating disk method at 37 degrees C in LISP SIF/FaSSIF and various concentrations of bicarbonates. Theoretical models including an improved reaction plane model and a film model were applied to estimate the surrogate phosphate buffers equivalent to the bicarbonates. Experimental results show that the intrinsic dissolution rates of ketoprofen and indomethacin in LISP and FaSSIF phosphate buffers are 1.5-3.0 times that in the 15 mM bicarbonates. Theoretical analysis demonstrates:rates that the buffer differential is largely dependent on the drug pK(a) and second en solubility, and weakly dependent on the drug diffusivity. Further, in accordance with the drug pK(a), solubility and diffusivity, a simple phosphate surrogate was proposed to match an average bicarbonate. value (15 mM) of the upper gastrointestinal region. Specifically, phosphate buffers of 13-15 mM: and 3-4. mM were recommended for ketoprofen and indomethacin, respectively. For both ketoprofen and indomethacin, the intrinsic dissolution using the phosphate surrogate buffer closely approximated the 15 mill bicarbonate buffer. This work demonstrates the; substantial difference between pharmaceutical phosphates and physiological bicarbonates in determining the drug intrinsic dissolution rates of BCS II weak acids, such as ketoprofen and indomethacin. Sur.,agate phosphates were recommended in order to closely reflect the in vivo dissolution of ketoprofen and indomethacin in gastrointestinal bicarbonates, which has significant implications for defining buffer systems for BCS II weak acids in developing in vitro bioequivalence c dissolution methodology.