Lysis of human red blood cells. 3: Effect of contact time on surfactant-induced hemolysis.

The percent hemolysis induced by various surfactants was determined as a function of the formulation composition and formulation: blood contact time using the dynamic in vitro method of Krzyzaniak et al. (1). The amount of hemolysis induced by nonionic surfactant formulations is shown to be relatively low and to increase only slightly with contact time. However, when ionic surfactant formulations are used, hemolysis is shown to increase dramatically with surfactant concentration and to be sigmoidally related to the logarithm of contact time. Since surfactant-induced hemolysis is dependent on both the surfactant concentration and the contact time, intravascular hemolysis must be evaluated using an in vitro method that simulates the intravenous injection site. With this information, hemolytically safe surfactant formulations can be developed for intravenous administration.

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.

Lysis of human red blood cells 1: Effect of contact time on water induced hemolysis.

A dynamic in vitro method for the determination of the degree of hemolysis induced by parenteral formulations is presented. This method utilizes a dual syringe pump apparatus that enables the mixing of a formulation with blood in various ratios and for various contact times. Formulations with varying tonicity were used to test the method. Hemolysis is shown to be directly related to both the hypotonicity of the test solution and the contact time. The proposed method makes it possible to evaluate the hemolytic effects of parenteral formulations at physiologically realistic contact times and formulation:blood ratios.

Self-association of dexverapamil in aqueous solution.

The pKa and intrinsic solubility of monomeric dexverapamil were determined from its pH-solubility profile to be 8.90 and 6.6 x 10(-5) M, respectively. The solubility of dexverapamil below pH 7.0 was higher than expected on the basis of the aforementioned values. This unusually high solubility is believed to be due to the self-association of cationic dexverapamil. The apparent pKa of the self-associated drug is estimated to be approximately 7.99. The self-association of dexverapamil hydrochloride is supported by the fact that it is surface active and that it increases the solubility of both naphthalene and anthracene in aqueous solutions. The dependence of the drug solubility on pH and the solubilization of naphthalene and anthracene as a function of ionized drug concentration suggest that the self-associated dexverapamil is a cationic dimer.