Agam R. Sheth

Exploring the Formation of Multiple Layer Hydrates for a Complex Pharmaceutical Compound

The pharmaceutical compound A, 3-{2-oxo-3-[3-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)propyl]imidazolidin-1-yl}-3(S)-(6-methoxypyridin-3-yl)propionic acid, is known to exist in five different crystalline forms that differ in the hydration state ranging from the anhydrous desolvate over hemihydrate, dihydrate, and tetrahydrate forms to the pentahydrate. The formation of the higher hydrates and the concomitant lattice expansion leads to undesirable tablet cracking at higher humidities. In this work, particle-based simulation techniques are used to explore the hydrate formation of compound A as a function of humidity. It is found that a simulation strategy employing Monte Carlo simulations in the isobaric-isothermal and Gibbs ensembles and transferable force fields, which are not parametrized against any experimental data for compound A, is able to yield satisfactory crystal structures for the anhydrate and pentahydrate and to predict the existence of all five hydrates.

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

(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.