title: Core size determination and structural characterization of intravenous iron complexes by cryogenic transmission electron microscopy.
abstract: Understanding physicochemical properties of intravenous (IV) iron drug products is essential to ensure the manufacturing process is consistent and streamlined. The history of physicochemical characterization of IV iron complex formulations stretches over several decades, with disparities in iron core size and particle morphology as the major source of debate. One of the main reasons for this controversy is room temperature sample preparation artifacts, which affect accurate determination of size, shape and agglomeration/aggregation of nanoscale iron particles. The present study is first to report the ultra-fine iron core structures of four IV iron complex formulations, sodium ferric gluconate, iron sucrose, low molecular weight iron dextran and ferumoxytol, using a cryogenic transmission electron microscopy (cryo-TEM) preservation technique, as opposed to the conventional room temperature (RT-TEM) technique. Our results show that room temperature preparation causes nanoparticle aggregation and deformation, while cryo-TEM preserves IV iron colloidal suspension in their native frozen-hydrated and undiluted state. In contrast to the current consensus in literature, all four IV iron colloids exhibit a similar morphology of their iron oxide cores with a spherical shape, narrow size distribution and an average size of 2nm. Moreover, out of the four tested formulations, ferumoxytol exhibits a cluster-like community of several iron carbohydrate particles which likely accounts for its large hydrodynamic size of 25nm, measured with dynamic light scattering. Our findings outline a suitable method for identifying colloidal nanoparticle core size in the native state, which is increasingly important for manufacturing and design control of complex drug formulations, such as IV iron drug products.
authors.affiliation: Division of Biology, Chemistry and Materials Science, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD 20993, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Division of Therapeutic Performance, Office of Research Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Petrochenko
authors.affiliation: Division of Biology, Chemistry and Materials Science, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD 20993, United States.
authors.forename: Lynn
authors.initials: L
authors.lastname: Chen
authors.affiliation: Division of Therapeutic Performance, Office of Research Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, United States.
authors.forename: Sook Yee
authors.initials: SY
authors.lastname: Wong
authors.affiliation: Division of Therapeutic Performance, Office of Research Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, United States.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Absar
authors.affiliation: Division of Therapeutic Performance, Office of Research Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, United States. Electronic address: stephanie.choi@fda.hhs.gov.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Choi
authors.affiliation: Division of Biology, Chemistry and Materials Science, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD 20993, United States. Electronic address: jiwen.zheng@fda.hhs.gov.
authors.forename: Jiwen
authors.initials: J
authors.lastname: Zheng
mesh_terms: D061605:Administration, Intravenous; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004339:Drug Compounding / Q000379:methods; D000067493:Dynamic Light Scattering; D005290:Ferric Compounds / Q000737:chemistry*; D000077605:Ferric Oxide, Saccharated; D052203:Ferrosoferric Oxide / Q000737:chemistry*; D005296:Ferrous Compounds / Q000737:chemistry*; D005937:Glucaric Acid / Q000737:chemistry*; D007505:Iron-Dextran Complex / Q000737:chemistry*; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D010316:Particle Size; D013696:Temperature
chemical_list: D005290:Ferric Compounds; D005296:Ferrous Compounds; D007505:Iron-Dextran Complex; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid; C011819:ferrous gluconate; D052203:Ferrosoferric Oxide
keywords: Core size; Cryo-TEM; Intravenous iron; Nanoscale pharmaceutics; Physicochemical characterization