Relationship between polysorbate 80 solubilization descriptors and octanol-water partition coefficients of drugs.

The molar solubilization capacities (kappa) and the molar micelle-water partition coefficients (K(M)(N)) in Polysorbate 80 of several drugs (including barbiturates, steroids, and benzoic acid derivatives) are related to their log octanol-water partition coefficients (logP). Both kappa and K(M)(N) values were calculated from solubility versus Polysorbate 80 concentration profiles, which were either experimentally determined or obtained from the literature. There is a linear relationship between logP of the tested compounds and the logarithm of the molar micelle-water partition coefficient (logK(M)(N)). On the other hand molar solubilization capacities are nearly independent of logP. It is shown that the ability of Polysorbate 80 to solubilize a drug can be predicted from its logP value.

Buffer capacity and precipitation control of pH solubilized phenytoin formulations.

The main objective of this investigation is to develop a phenytoin (DPH) intravenous formulation that does not precipitate upon dilution. The effect of the buffer capacity at pH 12 of several DPH formulations on the extent and lag-time of DPH precipitation upon dilution with Sorensen's phosphate buffer (SPB) is evaluated. DPH precipitation was evaluated by means of static and dynamic in vitro dilution methods. It is shown that an increase in the formulation buffer capacity decreases substantially the extent of DPH precipitation and increases the lag-time for precipitation. In addition, a comparison between static and dynamic in vitro methods to measure precipitation is presented.

Degradation kinetics of 4-dedimethylamino sancycline, a new anti-tumor agent, in aqueous solutions.

The kinetics of degradation of the new anti-tumor drug, 4-dedimethylamino sancycline (col-3) in aqueous solution at 25oC were investigated by high-pressure liquid chromatography (HPLC) over the pH-range of 2-10. The influences of pH, buffer concentration, light, temperature, and some additives on the degradation rate were studied. The degradation of col-3 was found to follow first order kinetics. A rate expression covering the degradation of the various ionic forms of the drug was derived and shown to account for the shape of the experimental pH-rate profile. Under basic conditions, the degradation of col-3 involves oxidation, which is catalyzed by metal ions and inhibited by EDTA and Sodium bisulfite.

Spectrophotometric determination of acidity constants of 4-dedimethylamino sancycline (Col-3), a new antitumor drug.

A spectrophotometric technique was used to determine the acidity constants of 4-dedimethylamino sancycline (Col-3), a new antitumor drug. The apparent pKa values of Col-3 in 0.5% methanol aqueous media at approximately 25 degrees C with a constant ionic strength of 0.2 were calculated manually and graphically to be 5.64 +/- 0.17 (pKa1) and 8.35 +/- 0.07 (pKa2). In addition, the computer program SQUAD was used to confirm Col-3 pKa values. The pKa values obtained by SQUAD were pKa1 5.63 +/- 0.14 and pKa2 8.39 +/- 0.04. These results are in agreement with the tetracycline-like structure of Col-3.

Solubilization of diazepam.

Several attempts to increase diazepam solubility are in the literature. This study discusses these different solubilization approaches. Specific reference is given to the rationale in the application of pH control, cosolvency, surfactants, and cyclodextrins. It was found than cosolvency is a more attractive means of solubilizing diazepam than either pH control, surfactants, or cyclodextrins. Advantages, assumptions, and limitations of these diazepam solubilization techniques are also described.

Lysis of human red blood cells. 4. Comparison of in vitro and in vivo hemolysis data.

The dynamic in vitro method developed by the authors and other available in vitro methods were used to determine the degree of hemolysis induced by several cosolvent vehicles that have previously been evaluated in vivo. The in vitro data generated for each of these vehicles was compared with the in vivo hemolysis data to assess the ability of the method to estimate in vivo hemolysis. The results show that the in vitro data generated by the dynamic method are in agreement with the in vivo data for each vehicle. Therefore, the potential for formulations to induce intravascular hemolysis after injection can be determined by this dynamic in vitro method. With this information, hemolytically safe formulations can more easily be prepared.