Risk Assessment and Physicochemical Characterization of a Metastable Dihydrate API Phase for Intravenous Formulation Development

• Published in: Journal of pharmaceutical sciences Vol. 99; no. 12; pp. 4973 - 4981
• Main Authors: Mortko, Christopher J., Sheth, Agam R., Variankaval, Narayan, Li, Li, Farrer, Brian T.
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.12.2010; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Animals; beta-Lactamase Inhibitors; beta-Lactamases - chemistry; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Chemical Phenomena; Chemistry, Pharmaceutical; crystal engineering; Crystallization; Drug Stability; formulation; General pharmacology; hydrate; Hydrogen Bonding; injectables; Injections, Intravenous; Medical sciences; Molecular Structure; Molecular Weight; Particle Size; Pharmaceutical Preparations - administration & dosage; Pharmaceutical Preparations - chemistry; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; physical stability; physicochemical properties; preformulation; pseudopolymorphism; Solubility; Water - chemistry; pseudopolymorphism; injectables; particle size; physicochemical properties; formulation; solubility; hydrate; physical stability; crystal engineering; preformulation; Evaluation; Particle size; Stability; Pharmaceutical technology; Intravenous administration; Solubility; Formulation; Risk factor; Physicochemical properties; Hydrates
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1002/jps.22225

(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.