Equilibrium Aqueous Solubility Research Articles

Numerical modeling of three-dimensional contaminant migration from dissolution of multicomponent NAPL pools in saturated porous media

A three-dimensional model for contaminant transport resulting from the dissolution of multicomponent nonaqueous phase liquid (NAPL) pools in three-dimensional saturated subsurface formations is developed. The solution is obtained numerically by a finite-difference scheme, and it is suitable for homogeneous porous media with unidirectional interstitial velocity. Each dissolved component may undergo first-order decay and may sorb under local equilibrium conditions. It is also assumed that the dissolution process is mass transfer limited. The nonaqueous phase activity coefficients of the NAPL pool components are evaluated at each time step. The model behavior is illustrated through a synthetic example with a NAPL pool consisting of a mixture of TCA (1,1,2-trichloroethane) and TCE (trichloroethylene). The numerical solution presented in this work is in good agreement with a recently developed analytical solution for the special case of a single component NAPL pool. The results indicate the importance of accounting for the necessary changes in the organic phase activity which significantly affects the equilibrium aqueous solubility.

Formulation assessment of MK-886, a poorly water-soluble drug, in the beagle dog

MK-886 is an orally active leukotriene biosynthesis inhibitor which may have therapeutic benefits in inflammatory diseases. The compound is the sodium salt of an organic acid with low aqueous equilibrium solubility and potentially poor oral absorption characteristics. Since there is no adequate in vitro method of predicting oral bioavailability for such poorly water-soluble compounds, assessment of formulations was conducted in vivo. The beagle dog was chosen as an animal model to select a suitable dosage form with good absorption characteristics. Dosage form performance was evaluated by comparing the following pharmacokinetic parameters: area under the plasma concentration vs time curve (AUC), peak plasma concentration ( C max ) and the time required to reach this peak ( T max ). Since no intravenous formulation was available, oral absorption from the different solid and liquid soft gelatin capsule formulations was evaluated relative to the absorption from a reference oral solution of MK-886 in PEG 400. Oral absorption of MK-886 in PEG 400 solutions was independent of solution concentration within the 15-fold range of concentration tested and was not affected by encapsulating the solutions in a soft gelatin shell. Food or co-administration of an alkalizing agent had no effect on the absorption of MK-886 from the soft gelatin capsules. Solid oral dosage forms, both capsules and tablets, had similar absorption characteristics to those of the PEG 400 solutions when the drug was granulated with an aqueous solution of polyvinylpyrrolidone (PVP), a hydrophilic polymer. PVP-granulated solid oral dosage forms had superior absorption characteristics when compared with a dry filled capsule of ungranulated drug.

Oral bioavailability and in situ absorption of etoposide in rat

Etoposide, an anticancer drug, has low oral bioavailability in humans which is due to low equilibrium aqueous solubility, slow dissolution rate, and instability at pH 1.3. Etoposide coprecipitate with PEG 8000 in a ratio of 1:10 (PEG weight fraction of 0.91) increased the solubility 2-fold and dissolution rate 42-fold. The oral bioavailability study of etoposide formulations was conducted in male Sprague-Dawley rats using a balanced crossover design. The absolute oral bioavailability of etoposide from coprecipitate, solution and powder was 5.56 ± 2.32, 10.16 ± 7.11 and l.29 ± 0.62%, respectively. No significant difference in oral bioavailability between solution and coprecipitate formulation was found but both were significantly higher than that of etoposide powder. The variability in serum concentrations and oral bioavailability of etoposide from coprecipitate formulation was much smaller than that from solution formulation. The very low extent of etoposide absorption even from a solution formulation (10.16%), in contrast to that in humans, suggested that factors other than the physicochemical properties may be responsible for the poor oral absorption of etoposide in rat. The in situ absorption studies in rats demonstrated very poor absorption of etoposide from stomach and the whole intestine by both Doluisio and Levine techniques. Bile salt (sodium taurocholate at 10 mM) reduced etoposide absorption. Thus, results from the in situ and in vivo absorption studies suggested that etoposide absorption is permeation rate limiting in rat. Therefore, rat may not be a good animal model for studying etoposide absorption from oral formulations with improved dissolution rate of etoposide.

Preformulation study of etoposide: identification of physicochemical characteristics responsible for the low and erratic oral bioavailability of etoposide.

Preformulation studies of etoposide, including pH-solubility profile, partition coefficient, pH-stability profile, and in vitro dissolution kinetics, were conducted to identify the responsible factor(s) for the low and erratic oral bioavailability of etoposide. A stability-indicating high-performance liquid chromatographic (HPLC) assay was used for drug monitoring. The equilibrium aqueous solubility of etoposide at 37 degrees C was low, 148.5-167.25 micrograms/ml, and did not vary over the pH range of 2 to 6. The pH-stability profile indicated rapid degradation of etoposide at pH 1.3 and 10, with degradation half-lives of 2.88 and 3.83 hr, respectively, at 25 degrees C. The half-life at pH 7.30 was 27.72 days. Maximum stability at 25 degrees C was reached at pH 5 to 6.15, with half-lives of 63 and 49.5 days, respectively. The intrinsic dissolution rate, determined on a Wood's apparatus, was slow, 0.0094 mg/min/cm2, while the etoposide partition coefficient between n-octanol and water was 9.94. Therefore, etoposide absorption appears to be dissolution rate limited rather than permeation rate limited. The low equilibrium aqueous solubility, slow intrinsic dissolution rate, and chemical instability at pH 1.3 could account for the low oral bioavailability.

Fresemide crystal forms; solid state and physicochemical analyses

The diuretic frusemide has been reported to occur only in one crystal form (frusemide I). This work details the production and initial characterisation of a second crystal form (fresemide II). The formation of frusemide II was shown to be solvent dependent, being recrystallised by a solvent-evaporation process from methanol or ethanol and inhibited by the addition of water (5% v/v level). X-Ray powder diffraction patterns indicated differences in the crystal packing of two forms whilst analysis of DSC thermograms defined changes in the melting/degradation event and a small endothern, occurring only in frusemide I, 81°C below the melting endotherm. Infrafed (IR) spectral changes included marked shift corresponding to the sulphonamide NH and S stretching vibrations suggesting the presence of an altered hydrogen bonding sequence frusemide II crystal. Solid state 13C-CP/MAS analyses of frusemide I and II revealed marked differences in the chemical environments of specific carbon atoms reflecting a change in molecular conformation. In addition, a two component T 1 ϱ relaxation time indicated domains within the frusemide II crystalline form possessing different degrees of order or rigidity. The physicochemical consequences of the solid state changes in frusemide II include a 63% increase in aqueous equilibrium solubility and a 58% increase in the dissolution rate from constant surface area discs, relative to frusemide I.

Dissolution and Ionization of Warfarin

It has been shown in recent studies that warfarin exists in the solid state and in some nonaqueous solvents as a cyclic hemiketal. The present study was undertaken to investigate the ionization and ionization kinetics of warfarin, to confirm the probable existence of the cyclic hemiketal in aqueous solution, and to determine the possible consequences of the cyclic hemiketal to acyclic enol equilibrium and ionization kinetics on the dissolution rate of warfarin. The equilibrium aqueous solubility of un-ionized warfarin acid at 25°C and ionic strength 0.5 (with potassium chloride) was found to be 1.28 × 10−5 M, and its observed macroscopic pKa was 5.03–5.06, depending on the method of determination. By comparing the aqueous pKa of warfarin to phenprocoumin, a hydroxycoumarin that cannot exist in the cyclic hemiketal form, the hemiketal-acyclic enol ratio was estimated to be ~20:1. By stop-flow spectrophotometry, the ionization rate of warfarin (pH 3.5 jumped to pH 6.5) was found to have a t1/2<1–2×10−3 s. The dissolution rate of warfarin from a rotating disk (600 rpm), as a function of pH, was measured under nonbuffered but pH-stat conditions (μ = 0.5 with potassium chloride). The pH-dissolution rate profile for warfarin agreed with that calculated from an equation derived previously to describe the dissolution of instantaneous ionizing acids, i.e., the profile was not perturbed from that expected from an acid of aqueous solubility 1.28 × 10−5 M (un-ionized form) and pKa 5.06.