Stability and microbiological properties of a new formulation of epoprostenol sodium when reconstituted and diluted

Olivier Lambert1, Dirk Bandilla1, Rupa Iyer2, Leonore Witchey-Lakshmanan3, Nagesh Palepu41Actelion Pharmaceuticals Ltd, Allschwil, Switzerland; 2TPM Laboratories Inc, Cherry Hill, NJ, USA; 3Pharma CMC/IP, Piscataway, NJ, USA; 4SciDose LLC, Amherst, MA, USAPurpose: Epoprostenol, used for the treatment of pulmonary arterial hypertension (PAH), has a number of limitations related to its short half-life in aqueous solution. The aim of this study was to evaluate the stability and microbiological properties of a new formulation, namely epoprostenol sodium with arginine and mannitol excipients (epoprostenol AM; Veletri®; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland).Methods: Stability and microbiological properties of epoprostenol AM were investigated at 5°C, 25°C, and 30°C over a range of concentrations (3000–30,000 ng/mL) when reconstituted and immediately diluted with sterile water for injection (SWI) or sterile saline (sodium chloride 0.9%) for injection (SSI). Stability (change in potency over time) for up to 72 hours at 25°C and 30°C was measured immediately following dilution and after storage at 5°C. Shelf-life was assessed by determining the maintenance of potency over time relative to initial potency. For microbiological testing, diluted samples of epoprostenol AM were inoculated with a range of bacteria, yeasts, and molds for up to 14 days at 5°C or 4 days at 25°C.Results: Epoprostenol AM reconstituted and immediately diluted to the required concentration with SWI or SSI was stable for up to 3 days at 25°C and up to 7 days at 5°C depending on the concentration. None of the diluted epoprostenol AM solutions supported microbial growth for any of the six organisms tested for up to 14 days.Conclusions: Epoprostenol AM has improved thermal stability and does not support the growth of any microorganism tested for up to 14 days. This extended stability under ambient conditions has the potential to improve convenience for patients.Keywords: stability, epoprostenol, formulation, microbial activity, diluents, pulmonary arterial hypertensio

The use of photopolymers as retaining frits and monoliths for electrochromatography in capillaries or microfluidic devices and some selected applications

This work explores the use of two different organic photopolymers for electrochromatography in the capillary format and also demonstrates their incorporation into a microfluidic platform. The first photopolymer studied functioned as a retaining frit for silica-supported, microparticulate stationary phase. After using the photopolymerization procedure in the capillary format the retaining frits were successfully integrated into the microfluidic platform. However, packing the microfluidic device with stationary phase particles could not be accomplished. A second photopolymer possessing C 4 -functionalities was therefore investigated as a porous stationary phase. It could be incorporated as a monolith in capillaries and thereby avoided the packing difficulties associated with individual particles and polymer retaining frits. Six polyaromatic hydrocarbons were baseline-separated within two minutes on this monolithic column. The monolith was also successfully created in the microfluidic format as verified by the separation of two fluorescent dyes. Due to the high cost of microfluidic devices the properties of the monolith were studied primarily in the capillary format. Van Deemter plots revealed the potential to use high mobile phase velocities without sacrificing resolution. Hydrodynamic and electrokinetic flow measurements gave insights into the porosity and tortuosity of the polymer by non-destructive means. Additionally, scanning electron microscopy and atomic force microscopy were employed to elucidate the microscopic structure and evaluate the pore size. The dependence of the electroosmotic flow on percentage and type of organic solvent, pH, ionic strength and concentration of sulfonate moieties in the polymer was measured. Various applications were surveyed with an emphasis on the separation of proteins. Their separation also served to evaluate the manufacturing process in terms of inter - and intra -capillary reproducibility. By comparing capillary electrochromatography, capillary electrophoresis and micro-LC it was found that chromatography is not the major contributor to the overall CEC separation of proteins. However, the monolithic columns demonstrated very good reproducibility as could be seen by using serum proteins as probes. Separations of small molecules were shown to be greatly based on a chromatographic separation mechanism. These applications included quality assessment in the synthesis of anthracene-2;3-dialdehyde, the separation of oligonucleotides and the separation of non-steroidal anti-inflammatory drugs