Particulate Study on NeoProfen, a Neonatal Injectable Product

Abstract

NeoProfen or sterile ibuprofen L-lysine at 10 mg/mL ibuprofen, in 2 mL single-use Type I glass vials is often a first choice medication used to close a patent ductus arteriosus in neonatal patients from 500 to 1500 g body weight. Visible particulate matter was found in vials that were placed on a commercial stability program prior to the approved expiration date of 2 years. A combination of instrumental techniques including inductively coupled plasma–mass spectrometry, x-ray photoelectron spectroscopy, scanning electron microscopy energy dispersive x-ray spectrometry, and Raman and Fourier transform infrared microspectroscopy was used to evaluate stability, pilot batch and packaging samples in a root cause investigation. The particulate matter was shown to consist largely of ibuprofen aluminum salts of various stoichiometries. It developed over time by a substitution mechanism, in which the ibuprofen anion in solution reacts with the aluminum oxide network of the borosilicate glass giving the ibuprofen aluminum salt with =Al-OH remaining in the network. For corrective action an alternate Type I borosilicate glass vial with interior coating, not found in the original vial, was chosen for the product to prevent this occurrence.

LAY ABSTRACT: NeoProfen (sterile preservative-free ibuprofin L-lysine at 17 mg/mL in a single-use glass vial) is used to close a clinically significant patent ductus arteriosus in premature infants no more than 32 weeks gestational age. The neonatal population is especially sensitive to outside chemical, physical and environmental conditions because of incompletely developed organ systems, low birth weight and other underlying conditions. Two batches of this product were voluntarily recalled by the manufacturer, Lundbeck, and investigated for the source of particulate matter observed during a commercial stability testing program. This was found to result from an interaction between the product and the Type I borosilicate glass vial where ibuprofen substitutes for the aluminum oxide network in the glass, forming an ibuprofen aluminum hydroxide salt as particulate. In order to prevent this salt formation an alternate glass vial was chosen which had interiors treated using a chemical vapor deposition technique. These vials were found to preserve NeoProfen quality properties during short term stress and medium term stability studies.