Preparation and characterization of gelatin sponge millispheres from air-in-water-in-oil-type emulsions.

A novel method for the preparation of gelatin sponge millispheres (GSMs) for biomaterials such as embolic agents and cell scaffolds was developed using an air-in-water-in-oil-type emulsion. The droplets, consisting of a foamy gelatin suspension in caprylic triglyceride, were gelled and rinsed with isopropanol. Sonication and depressurization were used during the rinsing process to create interconnected pores. GSMs cross-links created over 4 h at 155 degrees C without any agent were insoluble and had short and long diameters of 1.1 +/- 0.2 mm and 1.3 +/- 0.2 mm, respectively. The residual isopropanol and caprylic triglyceride were <0.05% (w/w) and <1% (w/w) respectively. The level of bacterial endotoxins in the extracts was below 0.025 EU/ml, and no bacterial or fungal growth was found during sterility testing. The GSMs produced using this method were considered to meet the basic requirements of embolic agents.

Solid-state compatibility studies using a high-throughput and automated forced degradation system.

As the number of pharmaceutical candidate compounds increases, so does the need for development workflow that is capable of handling more compounds in shorter times. In this paper, the establishment of a high-throughput automated powder compatibility testing system is reported. The integrated robotic system automatically dispenses, weighs, and stores powder samples, and extracts and analyses drug substance using ultra-performance liquid chromatography (UPLC). Although automation of powder testing systems is generally accompanied by difficulties in accuracy and precision, mass tracking at every unit operation allowed the system to be validated. In a standard procedure, drug substance and an excipient were dispensed 1:1 (w/w), stored at 70 degrees C for 9 days, dissolved in solvents, and analyzed to examine the degradation of drug substance and the increases in related substances. The robot quantitatively discriminate between initial conditions of the incompatible powder mixtures of aspirin and magnesium stearate (Mg-St) prepared with or without the use of a whisk and shaker system, demonstrating the capability for evaluating powder mixtures with varying degrees of homogeneity where the contact area between excipient and drug substance differs. Differential scanning calorimetry (DSC), however, did not clearly distinguish between those powder samples, indicating that DSC is less sensitive to powder conditions. The incompatibility results of aspirin and Mg-St were comparable to those reported previously, demonstrating that the automated testing system is reliable. The robot reduced manual work to one sixth and cut down on the costs of outsourcing. An extensive impact is anticipated on development workflows because this system is applicable not only to compatibility testing but also to analytical method development for drug products.

Excipient hydrolysis and ester formation increase pH in a parenteral solution over aging.

Recently, the number of drug substances that are poorly water-soluble has increased dramatically. This makes improving solubility one of the most critical tasks in pharmaceutical development today. In this study, the physicochemical stability of an injectable solution of conivaptan hydrochloride salt was investigated. Because its free form is hydrophobic, the drug substance was solubilized in a co-solvent system, 40% of which was composed of different alcohols. Since the free form is also alkaline, lactic acid was added to the co-solvent system to further improve its solubility. Remarkably, the pH of the solution was found to increase gradually over time. Considering the physicochemical nature of the drug substance, uncontrolled increases in pH would pose a potential threat of reducing solubility and forming precipitates. For this reason, a risk evaluation was performed. The evaluation revealed that the pH increase was caused by the hydrolysis of lactic acid oligomers as well as by the ester formation occurring between lactic acid and the alcohols. High concentrations of lactic acid supplied as an excipient usually contain lactic acid oligomers, which are hydrolyzed into lactic acid monomers upon dilution with water. Commercial software was used to determine the pK(a) values of the lactic acid oligomers, which were found to be lower than that of lactic acid monomers. This indicates that hydrolysis causes the pH to increase. Ester formation consumes the acid, which also causes the pH to increase. However, both hydrolysis and ester formation equilibrated by the 16-month time point when stored at 25 degrees C. This information allowed the upper limit of the pH increase to be determined molecularly, thereby ensuring product quality through the prevention of precipitate formation due to reduced solubility. Increased awareness of the importance of risk evaluation in pharmaceutical development is critical as these kinds of chemical reactions between excipients constitute a potential risk factor, but tend to be overlooked.