Crystallization and Solid-State Transformation of Pseudopolymorphic Forms of Sodium Naproxen

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Kim, Young-soo
Rousseau, Ronald W.
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Incorporation of water molecules in the crystal structure of an organic compound has strong effects on its physical and chemical properties. Therefore, the study on stability of water-incorporated pharmaceutical compounds and mechanisms of hydration and dehydration is very important for the pharmaceutical industries. The main goals of the present research project were quantitative description of the crystallization and solid-state transformations of pseudopolymorphs of sodium naproxen in order to provide fundamental information concerning stability of the pseudopolymorphic forms. Furthermore, macroscopic phenomena of size reduction and anisotropic water-removal by dehydration were rationalized by microscopic aspects of crystal lattice structures. The heats of solution for each pseudopolymorph were estimated by fitting the solubility data with the vant Hoff equation, and their use was extended by the thermodynamic cycle developed in the present study. According to the thermodynamic cycle, for an enantiotropic system, a form with a lower degree of hydration always has the lower heat of solution than a form with a higher degree of hydration, implying that a form with a lower degree of hydration is more stable. The relative stabilities of the dihydrated, the monohydrated, and the anhydrous sodium naproxen at 0% relative humidity were investigated by dehydration of the dihydrated form and powder X-ray diffraction. The monohydrate is more stable than the dihydrate and the result was supported by isothermal TGA experiments. This research explained why powder-like crystals of the anhydrous sodium naproxen were produced by dehydration of hydrated forms. The surfaces of the dehydrated crystals displayed cracks aligned along the b-axis of the monohydrate. These cracks made the anhydrous crystals, which were produced from the monohydrated species, very brittle and, eventually, such crystals were disrupted into much smaller entities. In addition, the existence of water channels in the unit cells of the monohydrate facilitates the dehydration in a direction more rapidly, especially, along the b-axis of the monohydrate. Rapid removal of water in a specific direction caused anisotropic dehydration.
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