Simulating fasted human intestinal fluids: understanding the roles of lecithin and bile acids.

The purpose of this work is to evaluate the roles of lecithin and bile salts in a new generation of fasted simulated small intestinal fluid (FaSSIF-II), thus enhancing the closer mimic of simulated fluids to the real human intestinal fluids (HIF) in drug discovery and drug product development. To assess the effects of lecithin in FaSSIF-II, solubility studies were conducted at 37 °C using four media including first generation simulated intestinal fluid (FaSSIF-I), FaSSIF-II, phosphate pH 6.5 buffer, and HIF. A total of 24 model compounds representing a wide range of biopharmaceutic properties were included. The drug solubility values measured in the FaSSIF-II were compared with those in FaSSIF-I, pH 6.5 buffer and HIF. To assess the effects of bile acids, solubility was measured for 4 compounds in the FaSSIF-I containing five different bile acids of various concentrations. The lecithin concentration in the FaSSIF-II is lowered from 0.75 mM to 0.2 mM. The results suggested that the FaSSIF-II is a better medium to reflect HIF, compared with pH 6.5 phosphate buffer and FaSSIF-I. Solubility of neutral compounds including atovaquone, carbamazepine, cyclosporine, danazol, diethylstilbestrol, felodipine, griseofulvin and probucol in FaSSIF-II showed improvement in predicting the in vivo solubility. The relative standard deviation (SD) of solubility measurement in FaSSIF-II is comparable with FaSSIF-I. For the acidic and basic tested compounds, the FaSSIF-II performs similarly to the FaSSIF-I. Experimental results showed that the level of bile salts typically is less than 5 mM under fasted state. Among the five studied bile acids, the conjugation (glycine or taurine) has no impact on the drug solubilization, while there may be a minimal effect of the degree of hydroxylation of the steroid ring system on solubilization. The lecithin concentration of 0.2 mM in FaSSIF-II has been demonstrated to closely represent HIF, for both neutral and ionizable compounds. In the composition of simulated intestinal fluids, the structure of bile acids has minimal effect, providing the flexibility of choosing one bile salt to represent complex in vivo bile acids.

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 of BCS II weak acids, and to recommend phosphate buffers equivalent to bicarbonates. The intrinsic dissolution rates of ketoprofen and indomethacin were experimentally measured using a rotating disk method at 37 degrees 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. Experimental results show that the intrinsic dissolution rates of ketoprofen and indomethacin in USP and FaSSIF phosphate buffers are 1.5-3.0 times that in the 15 mM bicarbonates. Theoretical analysis demonstrates that the buffer differential is largely dependent on the drug pK(a) and second on 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 buffers closely approximated the 15 mM 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. 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.

Particle diffusional layer thickness in a USP dissolution apparatus II: a combined function of particle size and paddle speed.

This work was to investigate the effects of particle size and paddle speed on the particle diffusional layer thickness h(app) in a USP dissolution apparatus II. After the determination of the powder dissolution rates of five size fractions of fenofibrate, including <20, 20-32, 32-45, 63-75, and 90-106 microm, the present work shows that the dependence of h(app) on particle size follows different functions in accordance with the paddle speed. At 50 rpm, the function of h(app) is best described by a linear plot of h{app} = 9.91sqrt d-23.31 (R(2) = 0.98) throughout the particle diameter, d, from 6.8 to 106 microm. In contrast, at 100 rpm a transitional particle radius, r, of 23.7 microm exists, under which linear relationship h(app) = 1.59r (R(2) = 0.98) occurs, but above which h(app) becomes a constant of 43.5 microm. Thus, h(app) changes not only with particle size, but also with the hydrodynamics under standard USP configurations, which has been overlooked in the past. Further, the effects of particle size and paddle speed on h(app) were combined using dimensionless analysis. Within certain fluid velocity/particle regime, linear correlation of h(app)/d with the square-root of Reynolds number (d\varpi/upsilon){1/2}, that is, h{app}/d = 1.5207 - 9.25 x 10{- 4} (d\varpi/n){1/2} (R(2) = 0.9875), was observed.

Solubilization and dissolution of insoluble weak acid, ketoprofen: effects of pH combined with surfactant.

This study investigated the combined effect of pH and surfactant on the solubility and dissolution of ketoprofen (KP), a highly permeable and an ionizable and water-poorly soluble drug in gastrointestinal tract. The equilibrium solubility of KP was determined in buffers at the pH range from 4.0 to 6.8 and sodium lauryl sulfate (SLS) concentrations from 0% to 2.0%. Its intrinsic dissolution rate was measured in the same media using a rotating disk apparatus. A simple additive model accounting for the free unionized KP and ionized KP(-) forms, and their corresponding micellar forms was employed to study the in vitro solubility and dissolution behavior. Non-linear regression analysis showed that the proposed model agreed well with the experimental data, with R(sq)=0.96 (P<0.0001) for the solubility study, and R(sq)=0.98 (P<0.0001) for the intrinsic dissolution rate measurement. The pK(a) and c(KP) values are estimated as 4.76+/-0.00 and 0.253+/-0.05 mg/mL, respectively, in good agreement with literature reports. The micellar solubilization coefficient k(*) for the unionized [KP](micelle) is 757+/-165 L/mol, whereas the value k(**) for the ionized [KP(-)](micelle) is 9.88+/-6.70 L/mol. The diffusion coefficients of various species: KP, KP(-), [KP](micelle), and [KP(-)](micelle), are 7.68 x 10(-6), 1.54 x 10(-6), 2.32 x 10(-7), and 2.13 x 10(-20)cm(2)/s, respectively. The maximum enhancement of solubilization is approximately 232-fold, while the maximum dissolution amplification is only 54-fold because of the smaller diffusivity of micellar species. The dramatic enhancement of in vitro solubility/dissolution attributable to an increase of pH and presence of SLS mimics the in vivo solubilization/dissolution behavior of KP along the gastrointestinal tract, when the pH increases from 1-2 in the stomach to 5-6 in the duodenum. The results suggest that the KP dissolves very rapidly in small intestine, implying that its absorption will be predominantly controlled by gastric emptying, and only minimally limited by the subsequent dissolution processes. This behavior is very similar to BCS I drugs, thus KP may be considered for possible waivers of bioequivalence.