title: Risk assessment and physicochemical characterization of a metastable dihydrate API phase for intravenous formulation development.
abstract: (1S,5R)-2-{[(4S)-azepan-4-ylamino]carbonyl}-7-oxo-2,6-diazabicyclo[3.2.0] heptane-6-sulfonic acid (Compound 1) is a β-lactamase inhibitor for intravenous administration. The objective of this preformulation study was to determine the most appropriate form of the API for development. Compound 1 can exist as an amorphous solid and four distinct crystalline phases A, B, C, and D in the solid state. Slurry experiments along with analysis of physicochemical properties were used to construct a phase diagram and select the most suitable form of the API for development. In aqueous formulations, the dihydrate form of the API was predominant and, due to the more favorable solubility and dissolution profile required for preclinical and clinical studies, a metastable form of the API was selected, and the risks associated with developing this form were evaluated.
authors.affiliation: Basic Pharmaceutical Sciences, Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey 07065, USA. christopher_mortko@merck.com
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Mortko
authors.forename: Agam R
authors.initials: AR
authors.lastname: Sheth
authors.forename: Narayan
authors.initials: N
authors.lastname: Variankaval
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Brian T
authors.initials: BT
authors.lastname: Farrer
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000737:chemistry; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004355:Drug Stability; D006860:Hydrogen Bonding; D007275:Injections, Intravenous; D015394:Molecular Structure; D008970:Molecular Weight; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry*; D012995:Solubility; D014867:Water / Q000737:chemistry; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry*
chemical_list: C556203:(1S,5R)-(((4S)-azepan-4-ylamino)carbonyl)-7-oxo-2,6-diazabicyclo(3.2.0)heptane-6-sulfonic acid; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004364:Pharmaceutical Preparations; D065093:beta-Lactamase Inhibitors; D014867:Water; D001618:beta-Lactamases