Layered Structure and Swelling Behavior of a Multiple Hydrate-Forming Pharmaceutical Compound

Investigation of one anhydrous and four hydrated forms of a pharmaceutical compound (1) using both single-crystal and high-resolution powder X-ray diffraction methods revealed a two-dimensional framework which, upon exposure to moisture, absorbed water between the layers, causing the lattice to expand by as much as 20% of the axial length along a. The single-crystal structure was solved and refined for the pentahydrate form in space group C2 with unit cell parameters a = 36.961(5) Å, b = 7.458(2) Å, c = 20.691(4) Å, β = 99.461(1)°, and V = 5626(4) Å3. In the single-crystal structure the water layers were parallel to the bc plane and sandwiched by the crystalline compound 1 framework. Upon a change of relative humidity, water goes in and out of the interlayer space with the retention of the layer structure of the development compound. Starting from the anhydrous form, each additional water of hydration increased the interlayer spacing of the pharmaceutical solid by ∼1.3 Å, half the size of a water molecule. In an exploratory formulation, this expansion of interlayer spacing caused tablets to crack upon storage at high relative humidity.