Abstract

REACTION OF ACRYLIC ACID LEACHING FROM PACKAGING COMPONENT WITH MOXIFLOXACIN HYDROCHLORIDE AND THE STRUCTURAL ELUCIDATION OF REACTION PRODUCT BY LC-MS-MS.

*Dr. Sandeep Zokande, Dr. Kavita Inamdar, Vikas Mane

ABSTRACT

Light density polyethylene (LDPE) has excessive rewards as a primary container closure system (CCS) to store ocular dosage forms due to its distinguished performance. As a regulatory requirement.[1] and to ascertain the safety and efficacy of drug products, extractables and leachables need to be studied by means of extreme polarity of organic solvents and aqueous phase at extreme acidic and basic pH. If extractables are above AET; those need to be classified as potential leachables and to be controlled in drug product as a quality attribute. Leachables are being scrutinized by a unique method to evaluate suitability of CCS. There is high possibility of interaction between drug product components with leachables and generates the degradation product / reaction product / adduct which may not be possible to estimate using method designed for leachables and as a drug product impurity using quality attribute “related substances” of drug product. This study illustrates that only extractables and leachables study is not adequate to ascertain the quality of CCS and product safety. Moxifloxacin ophthalmic solution was selected as a drug product for this study. Acrylic acid is commonly used in adhesive of label of product, printing ink and varnish hence it is selected as a slow migrant. Acrylic acid is a small molecule hence there is a high possibility of its penetration through semi permeable containers. Acrylic acid tends to form adduct due to the presence of N=H bond. The N=H bond is predominant in the structure of moxifloxacin. The reaction of acrylic acid with moxifloxacin is confirmed using placebo and solution of moxifloxacin hydrochloride. The reaction is monitored for formation of moxifloxacin adduct. The IUPAC nomenclature of moxifloxacin adduct is identified as “7-((4aS,7aS)-1-(2- carboxyethyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-1-cyclopropyl-6-fluoro-8-methoxy- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid” [Chemical Formula: C24H28FN3O6, Molecular Weight: 473.50] using universal LC-MS technique. The MS-MS analysis was used to provide mass spectroscopic fragments to support the confirmation of structure of moxifloxacin adduct. The product related degradation products are distinguished by various studies such as forced degradation, compatibility study, stress study and stability study of drug product. The intention of this study is to demonstrate the possibility of reaction between leachable and drug product packed in semipermeable CCS which may not be monitored as a product quality attribute and may be risk to the patient. This study helps to design the process to evaluate an anticipated degradation product / adduct to ensure drug purity, safety for patient and to design product specification well in advance during product development phase.

Keywords: Active Pharmaceutical Ingredient, Ophthalmic Drug Product, Stress study at strenuous condition, Leachable, Container closure system, Label, Leaflet, Carton, Migration, Adduct, LC-MS, MS-MS.