Physical Characterization of TRK-720 Hydrate, the Very Late Antigen-4 (VLA-4) Inhibitor, as a Solid Form for Inhalation: Preparation of the Hydrate by Solvent Exchange among Its Solvates and Mechanistical Considerations

TRK-720 has been under development as a dry powder inhaler (DPI) for treating bronchial asthma. DPI is a drug formulation of an active pharmaceutical ingredient (API) supported by carrier particles. On inhalation, the API particles dissociate from the carriers through physical stimulation and reach the lung through the humid upper airways, therefore, the API has to remain physically and chemically stable despite contact with carriers and low relative humidity. Also it should be pulverized into an appropriate size (1-10 mu m) for reaching the target region. To fulfill these requirements, API in crystal form is needed. Polymorphic screening using 42 solvents produced 9 solvates but not the target hydrate or ansolvate crystal. When the solvent was removed from each solvate, only methanolate could reproducibly be converted into hydrate by water vapor substitution. As the hydrate satisfied the above requirements for DPI, it was selected as a solid form for development. Also, the results of single crystal X-ray structural analyses and calculations of crystal packing energies, for five of the solvates, indicated that only the methanolate can be converted into the hydrate through solvent substitution. (C) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3986-4004, 2010