A New Hydrate of Cyclosporine: Structural and Physicochemical Characterization

This work highlights a new orthorhombic hydrate (Form 2) of cyclosporine (CsA), a widely used immunosuppressant. The uniqueness of this new form was established by powder X-ray diffractometry, solid-state nuclear magnetic resonance spectroscopy, and single crystal X-ray diffraction analysis. The crystal structure of this form was solved (P2₁2₁2₁, a = 12.639 Å, b = 19.758 Å, c = 29.568 Å, Z = 4). In addition, the solid-state properties of Form 2 were compared with other known crystalline forms of CsA by thermal analysis, water vapor sorption analysis, Fourier-transform infrared spectroscopy, and so on. These studies suggest that Form 2 is a nonstoichiometric hydrate with distinctive hydrogen bonding modes. More importantly, Form 2 is about an order of magnitude less soluble than the commercially available tetragonal form (Form 1). An interconversion map among various CsA solid forms was built by slurry experiments. Form 2 was the most stable form in aqueous systems, whereas the previously known orthorhombic hydrate (Form 3) was the predominant form in nonaqueous vehicles. While Form 2 as a lower solubility form poses greater challenge in bioavailability enhancement, the solid-state properties of this unique hydrate may provide new drug delivery opportunities.