Detection and Identification of an Unknown Impurity in Ephedrine HCl 5 mg/mL Cyclic Olefin Syringes: Formulation Development.

An unknown impurity was detected in in-house prepared ephedrine hydrochloride (HCl) 5 mg/mL prefilled sterilized syringes when applying a stability-indicating British Pharmacopoeia 2018 impurity method for ephedrine injection. Ultraviolet, chromatographic, mass spectral, and physicochemical methods were combined to identify the unknown impurity. The unknown impurity was identified as methcathinone, which is generated from ephedrine drug substance through an oxidation reaction. A formulation study, in which different process adjustments were tested, was carried out to reduce the amount of unknown impurity. Nitrogen gassing in combination with 0.05 M citrate buffer addition proved to be the most potent process adjustment in reducing methcathinone formation in ephedrine HCl 5 mg/mL prefilled sterilized syringes after 4 months of storage in the dark at room temperature (20 °C ± 5 °C). More detailed research on the long-term stability of the reformulated ephedrine HCl drug product is currently underway, with promising results for up to 9 months gathered already.

Prefilled Cyclic Olefin Sterilized Syringes of Norepinephrine Injection Solution Do Not Need to Be Stabilized by Antioxidants.

Norepinephrine is a potent α-sympathomimetic drug which plays an important role in the acute treatment of hypotension and shock. Commercially available norepinephrine solutions contain sodium metabisulfite (Na2S2O5) as an antioxidant. However, prefilled cyclic olefin polymer syringes are not compatible with sodium metabisulfite. The aim of this study was to develop a new formulation of 0.1-mg/mL norepinephrine solution without sodium metabisulfite which is chemically stable and sterile and can be stored in prefilled polymer syringes. Formulation studies were performed with 0.1-mg/mL norepinephrine solution with 0, 0.05, or 0.1% ascorbic acid added as antioxidant. The syringes were filled under nitrogen gassing, stored at 20 ± 5°C, and protected from daylight. Based on the formulation test results, the final formulation was defined and stability testing at 20 ± 5°C was performed measuring norepinephrine concentration, pH, clarity, color of the solution, subvisible particles, and sterility at time intervals up to 12 months. The norepinephrine concentrations at t = 22 weeks were 100.4%, 95.4%, and 92.2% for the formulations with no ascorbic acid and with 0.05% and 0.10% ascorbic acid, respectively. Three batches for the stability study were produced containing norepinephrine, sodium edetate, sodium chloride, and water for injections filled under nitrogen gassing and stored at 20 ± 5°C. Norepinephrine concentrations were respectively 98.8%, 98.6%, and 99.3% for batches 1, 2, and 3 at t = 12 months. It can be concluded that norepinephrine (0.1 mg/mL) solution without metabisulfite is stable for at least 12 months at room temperature when protected from daylight.

Bimodal Latex Effect on Spin-Coated Thin Conductive Polymer-Single-Walled Carbon Nanotube Layers.

We synthesize two differently sized poly(methyl methacrylate-co-tert-butyl acrylate) latexes by emulsion polymerization and mix these with a sonicated single-walled carbon nanotube (SWCNT) dispersion, in order to prepare 3% SWCNT composite mixtures. We spin-coat these mixtures at various spin-speed rates and spin times over a glass substrate, producing a thin, transparent, solid, conductive layer. Keeping the amount of SWCNTs constant, we vary the weight fraction of our smaller 30-nm latex particles relative to the larger 70-nm-sized ones. We find a maximum in the electrical conductivity up to 370 S/m as a function of the weight fraction of smaller particles, depending on the overall solid content, the spin speed, and the spin time. This maximum occurs at 3-5% of the smaller latex particles. We also find a more than 2-fold increase in conductivity parallel to the radius of spin-coating than perpendicular to it. Atomic force microscopy points at the existence of lanes of latex particles in the spin-coated thin layer, while large-area transmission electron microscopy demonstrates that the SWCNTs are aligned over a grid fixed on the glass substrate during the spin-coating process. We extract the conductivity distribution on the surface of the thin film and translate this into the direction of the SWCNTs in it.

Science- and risk-based strategy to qualify prefillable autoclavable syringes as primary packaging material.

OBJECTIVES: To develop a science and risk based strategy to qualify a prefillable autoclavable cyclic olefin polymer (COP) syringe as a container for multiple drug products in a hospital pharmacy setting METHODS: Different extraction studies were performed with different solution characteristics: phosphate buffer batches (Na2HPO4 / NaH2PO4 in NaCl 0.9%) at different pH values, NaCl 0.9% batches, isopropyl alcohol (IPA) 5% in water and batches with Water For Injections (WFI) at different pH values. The filled syringes were terminally sterilised. The syringes were stored at room temperature (20°C±5°C).Following different monographs of the European Pharmacopoeia several tests were performed on the different batches. Analyses were performed at t=0, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24 and 36 months for the general tests. For the subvisible particles, sterility and closure integrity a bracketing scheme was applied during 36 months. RESULTS: Low levels of extractables were measured for the different solutions. The test for subvisible particles, sterility and closure integrity all met predefined requirements. In the 5mL and 50mL syringes different concentrations of silicon were measured. Overall higher silicon concentrations were measured for the 50mL syringes. CONCLUSIONS: The chosen strategy for the qualification program provided an adequate understanding about the extractables that could leak from the syringes. The cyclic olefin polymer syringes including stopper and tip cap were found to be suitable as primary packaging materials for the production of water based products.