Toward anIn VivoDissolution Methodology: A Comparison of Phosphate and Bicarbonate Buffers

Abstract

Purpose 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 of BCS II weak acids, and to recommend phosphate buffers equivalent to bicarbonates. Methods The intrinsic dissolution rates of, ketoprofen and indomethacin, were experimentally measured using rotating disk method at 37°C in USP 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. Results Experimental results show that the intrinsic dissolution rates of ketoprofen and indomethacin, in USP and FaSSIF phosphate buffers are 1.5–3.0 times of that in the 15 mM bicarbonates. Theoretical analysis demonstrates that the buffer differential is largely dependent on the drug pKa and secondly on solubility, and weakly dependent on the drug diffusivity. Further, in accordance with the drug pKa, solubility and diffusivity, 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 buffers closely approximated the 15 mM bicarbonate buffer. Conclusions 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. Surrogate 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 dissolution methodology.

Hybrid aerogel preparations as drug delivery matrices for low water-solubility drugs

“…with pKa values of 4.40, 4.76 and 4.15 for Ibu, Ket and Trf, respectively (Sheng et al, 2009). Performed measurements gave an estimation of drugs solubility 257 under studied experimental conditions: at pH 2 and 37 ºC, measured solubility values were in the order of 0.06, 0.26 and 0.69 mg mL-1 for Ibu, Ket and 258 Trf(T), respectively, while at pH 6.7 and 37 ºC, the solubility of the three compounds was higher than 0.7 mg mL-1, which was the highest value assayed.…”

Evolution of a physiological pH6.8 bicarbonate buffer system: Application to the dissolution testing of enteric coated products

“…Phosphate buffer has an effective pKa of 7.19 and a resultant higher buffer capacity (23 mmol/L/∆pH) thus provides greater driving force for the acidic polymer dissolution than that of bicarbonate with a pKa of 6.31 and a much lower buffer capacity (3.1 mmol/L/∆pH). Sheng et al has also suggested that pKa differences in these two buffer species results in different buffer capacity at the solid-liquid interface; where phosphate buffer had about 23 % higher buffer capacity relative to the bicarbonate, at the same pH and buffer concentration [35]. Ionic strength of the dissolution media also have a profound effect on the reaction rate between the polymer film and the basic buffer species; a drastic change in the dissolution rate has been reported from enteric coated formulations with change in ionic strengths of the media [15,23,29].…”

Microparticulate polyelectrolyte complexes for gentamicin transport across intestinal epithelia

“…GM in vitro release from cross-linked and co-cross-linked microparticles was evaluated in a pH 3.0 medium for 2 h and, then, in pH 7.4 Tris-HCl buffer for 4 h in order to simulate the pH conditions of the gastrointestinal tract ( Figure 5). By considering that phosphate buffer species, having a chelating action on calcium, are disconnected with the principal physiological species in the human GI tract (Dressman & Reppas, 2000;Sheng et al, 2009), Tris-HCl buffer was selected instead of phosphate buffer. The cross-linked microparticles provided a three-phase profile showing a negligible GM release at pH 3.0 and a burst effect (∼ 60%) followed by a gradual release phase at pH 7.4.…”