Identification of an Adduct Impurity of an Active Pharmaceutical Ingredient and a Leachable in an Ophthalmic Drug Product Using LC-QTOF.

Impurity investigations are important in pharmaceutical development to ensure drug purity and safety for the patient. The impurities typically found in drug products are degradants or reaction products of the active pharmaceutical ingredient (API) or leachable compounds from the container closure system. However, secondary reactions may also occur between API degradants, excipient impurities, residual solvents, and leachables to form adduct impurities. We hereby report an adduct-forming interaction of API (moxifloxacin) with a leachable compound (ethylene glycol monoformate) in moxifloxacin ophthalmic solution. The leachable compound originated from a low-density polyethylene bottle used in the packaging of drug products. The adduct impurity was tentatively identified as 1-cyclopropyl-6-fluoro-7-(1-(2-(formyloxy)ethyl) octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (C24H28FN3O6, MW = 473.19621) using accurate mass LC-QTOF analysis. The mass accuracy error between the theoretical mass and the experimental mass of an impurity was found to be 0.2 ppm. An MS/MS analysis was utilized to provide mass spectrometry fragments to support verification of the proposed structure.

A case study demonstrating the migration of diethyl phthalate from an ancillary component to the drug product.

Phthalates are chemical compounds employed as plasticizers in the plastic industry and have been reported to migrate into drug products. The extent of their migration into the drug product depends upon various factors including the chemical nature of the migrant and the permeability of its packaging container. Migration of semi-volatile phthalates such as Diethyl phthalate (DEP) into drug products is often related to the primary and secondary packaging but due to its chemical nature, it could also migrate from an ancillary component. Therefore, it is not only important to screen the primary and secondary components, but also the ancillary materials that are used during the handling of drug products. In our study, we discovered an ancillary material (scotch tape) to be the source of DEP found in an ophthalmic drug product using orthogonal mass spectroscopy techniques (GC-MS and LC-MS). It is evident from our data that DEP migrated from the scotch tape into the drug product crossing the physical barriers provided by the primary (LDPE container closure system) and secondary packaging (carton and label). The tape was used as an ancillary material to wrap the packaged drug product units together for storage in the stability chamber. The primary and the secondary packaging of the drug product did not exhibit any traces of DEP. The aim of this report is to demonstrate how a chemical compound can migrate into the drug product from an ancillary source (which is not a part of its packaging) and adulterate a drug product. The impact of ancillary materials on drug products should be evaluated appropriately prior to their implementation.

Identification of leachable impurities in an ophthalmic drug product originating from a polymer additive Irganox 1010 using mass spectroscopy.

Pharmaceutical packaging employs a wide variety of polymers owing to their desirable features, but the compounds that could leach from the polymers into the drug products can pose serious health risks. Therefore, it is extremely important to identify such compounds so that they can be adequately quantified and evaluated for toxicological impact/safety assessments. Not only the polymer components and the additives should be considered as sources for leachable impurities, their reaction/degradation products should also be evaluated. Irganox 1010 is a common commercial antioxidant (polymer additive) used in the manufacturing of polyolefin materials for container closure systems. In our study, we identified two Irganox1010 related leachable impurities in an ophthalmic drug product using rapid and straightforward orthogonal mass spectroscopy (LC-MS and GC-MS) methods The identified impurities were 7,9-Di-tert-butyl-1 oxaspiro[4.5]deca-6,9-diene-2,8-dione and 3-[3,5-bis(tert-butyl)-1-hydroxy-4-oxocyclohexa-2,5-dienyl]propanoic acid which leached into the ophthalmic drug solution during storage. The analytical methods employed could potentially be used to identify the similar class of compounds as is or in drug products.