An opportunistic stability strategy; simulation with real data.

A multivariate modelling procedure is proposed in order to identify factors influencing stability, to estimate shelf-life, to select new batches for further stability testing and to evaluate changes in new batches. A model developed by the proposed procedure predicts the degradation rate constant as a function of storage temperature, pH, concentration and volume. The predicted rate constants were compared with prospectively measured rate constants, primarily from new batches stored under stress conditions, which emphasised batch differences earlier than storage under normal conditions. Strong deviations from expected rate constants led to extended testing of the batches concerned. The new data were used to upgrade the multivariate model. The procedure proposed led to the formulation of an opportunistic stability strategy (OSSY). Of the 15 batches of injectable solutions, nine batches are proposed tested by using OSSY. This led to an approximately 75% reduction in analytical measurements. Hold samples are recommended for storage under several stability conditions for back up analysis. In general, a multivariate stability model should be based on scientific data obtained from early studies, such as preformulation and formulation studies to provide both a qualitative and quantitative understanding of the mechanisms involved.

Physicochemical properties of iodixanol.

Iodixanol, the radiopaque in Visipaque, is a new nonionic, dimeric roentgen contrast medium for intravascualr use. Compared to aqueous solutions of nonionic monomers, which have higher osmolality than blood, aqueous solutions of iodixanol have a lower osmolality due to dimeric structure of the molecule. As a consequence of this advantageous property, solutions of all clinical concentrations of iodixanol can be made isotonic by the addition of salts of the key electrolytes sodium and calcium to the formulation. The viscosity of all iodixanol (Visipaque) solutions is less than or equal to that of iohexol (Omnipaque) 350 mg I/ml. Iodixanol itself is an amorphorus and hygroscopic solid which is freely soluble in water. Partition coefficients show that iodixanol is even more hydrophilic than the nonionic monomers such as iohexol. The high hydrophilicity and the good aqueous solubility of iodixanol are due to the hydroxyl group in the dimer linkage and the hydrophilic amide side chains of the molecule.

Formulation, stability and compatibility of iodixanol.

Iodixanol (Visipaque) is an isotonic, electrolyte-balanced roentgen contrast medium for intravascular use. The patented and well-proven formulation and the rationale for it are described, and the efficacy and safety are documented. The stability of iodixanol is well within the specifications under all relevant conditions, both in glass and polypropylene bottles; the product has a recommended shelf-life of at least 36 months when stored at room temperature and protected from light. Heating to body temperature before use is acceptable and recommendable, and storage at 37 degress C for 1 month does not jeopardize product quality. Iodixanol has no apparent immediate in vitro incompatibility reactions with drugs often used in connection with roentgen contrast examinations.

Handling of psilocybin and psilocin by everted sacs of rat jejunum and colon.

Psilocybin and psilocin at luminal concentrations of about 20 nmol/ml were incubated aerobically with everted sacs from rat jejunum and colon. When incubation was terminated, samples of the lumen and blood side solutions and of the intestinal tissue were analyzed for parent drug and metabolites by HPLC using a multidetector system. Both sacs caused hydrolysis of psilocybin to psilocin, but the rate was much faster in the jejunum than in the colon. Tissue uptake of intact psilocybin was negligible or absent, and no transfer to the contraside of the parent drug could be demonstrated. In contrast, psilocin, whether formed by hydrolysis or added as a substrate, was well taken up by both intestinal segments and transferred to the blood side. In the colonic psilocybin experiments, this uptake and transfer was limited by a low hydrolytic rate. The results indicate that psilocybin under in vivo conditions is absorbed predominantly as psilocin. No further metabolism of either drug was observed, as opposed to the complex metabolism pattern that has been reported for serotonin, a close chemical relative to psilocin.