Assessment of the stability of methotrexate in 0.9% sodium chloride IV admixtures.

摘要

Pharmaceutical compounding is the practice of creating a pharmaceutical product to meet the unique needs of a patient. Compounded pharmaceutical preparations are typically made per the prescription of a physician for individual patients. Compounding pharmacies are regulated by their state pharmacy boards and not by the FDA. However, drug shortages and increased prices from drug manufacturers for many commercially available drugs have forced clinics and hospitals to source their compounding needs to dedicated compounding pharmacies that make compounded drug products in bulk. This has been especially true for IV admixtures, which are always prepared by compounding pharmacists to accommodate the dosage and dosing schedules of specific patients. This increased demand has resulted in compounding pharmacies overextending themselves and operating at the capacity pharmaceutical manufacturers and even shipping their products across state borders. This has caused a regulatory concern as such operations are not regulated by the FDA.;While the laws to regulate compounding pharmacies have been amended, the practice of preparing IV admixtures of many drugs at a large scale and shipping them across state borders continues to be a practice. Therefore, there is a burden on the current healthcare system to maintain the safety and efficacy of compounded IV admixtures throughout the compounding process, shipment, and storage. Methotrexate (MTX) is a highly prescribed antimetabolite used to treat various cancers and serves as an essential drug to any healthcare system. MTX is commonly prepared in compounding pharmacies and to date its chemical stability in an IV admixture using 0.9% saline is unknown under certain conditions and durations of time.;An HPLC method was developed and validated to analyze a standard curve of MTX concentrations so that the degradation of MTX concentrations in an IV admixture that uses 0.9% saline as a vehicle could be determined. IV bags with MTX concentrations of 2.0 mg/mL were prepared and stored under four different conditions: Unjacketed at room temperature, refrigerated at 4°C, frozen at -20°C, and jacketed at room temperature for a total of 35 days. Samples were drawn from the IV bags at 1, 2, 3, 7, 14, 21, 28, and 35 days and analyzed in the HPLC to determine the degradation of MTX concentrations, if any. Forced degradation studies were also conducted exposing drug solutions of MTX at 2.0 mg/mL to extreme temperatures and highly acidic and basic pH to determine if degradants could be generated and also to confirm that any degradants did not interfere with the peak of MTX in the HPLC chromatogram. These studies also elucidated the extent of degradation that could occur and in the amount of time it would take to degrade to sufficient levels suggested by the FDA guidance for these studies.;The drug content in the MTX IV admixture from all of the four conditions was greater than 90% of the target concentration after 35 days, which is in the acceptable by the USP limit for being considered stable. The USP also recommends at least a loss of 10 to 30% of the active drug in any single condition during forced degradation studies for the assay to be considered stability-indicating. MTX when exposed to 30% hydrogen peroxide and when boiled to 90°C for 15 hours exceeded these requirements by degrading to 76.10% and 61.52% of the 2.0 mg/mL target concentrations, respectively.