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Determing the Influence of Moisture and Oxygen on the Physico-Chemical Properties of the Drug Molecule Using Software Modelling and Analytical Techniques H. Shah, K. Morris Long Island University Purpose The intent of this study is to test the hypothesis that the chemical stability of levothyroxine sodium pentahydrate depends upon the degree of hydration and/or the integrity of the crystal structure on dehydration. “Water of Crystallization” refers to the water that is found in the crystalline lattice of the compound and is known to be affected by the temperature & humidity conditions. This may lead to changes in the crystal structure, potentially affecting the potency of the drug product. Methods The three-dimensional crystal structure of Levothyroxine Sodium Pentahydrate will be studied using CSD, Material Studio and Mercury, to help estimate/anticipate the impact of hydration state on the structure. Most importantly, the ability of the lattice motif to persist as a dehydrated-hydrate will be related to the total strain on the structure. The sources of strain to be studied in Levothyroxine Sodium Pentahydrate include: 1. 2. 3. Angle strain: destabilization that results from distortion of bond angles from their normal values Torsional strain: destabilization that results from the eclipsing of bonds on adjacent atoms Van der Waals strain: destabilization that results when atoms or groups on nonadjacent atoms are too close to one another. XRPD, TGA, DSC, Moisture sorption analysis studies will be used to follow the structural changes at 0% & 100%, and in between,humidity conditions. Results Logistically, the internal energy of the lattice will be estimated in MS using the appropriate force fields to estimate the magnitude of change from the original structure upon computational dehydration. The experimental powder patterns were used to assess the degree of persistence of the original structure which will be coupled with chemical stability studies to test for correlations. The water content of levothyroxine Sodium Pentahydrate was determined through thermogravimetric analysis (TGA) And the potency of the Levothyroxine Sodium Pentahydrate & the formation of impurities in different conditions was determined using HPLC. Crystallographic analysis revealed the presence of subunits that are hydrogen bonded to each other and additional molecules of H2O present in the molecule. Absorption/desorption profile from moisture sorption analysis experiments performed by stepping the humidity (% RH) over a broad range at constant temperature helped us understand any structural changes in the molecule. Conclusion The waters of hydration seems to play an important role in stabilizing the molecular framework not visible to naked eye. The observation that the chemical stability of levothyroxine sodium pentahydrate is compromised upon dehydration is as demonstrated leaves open the question of the need for the persistence of the “open” channels to facilitate degradation and the question of the apparent plateau in the level of degradation . The same approach of study will also be explored to determine the applicability to other narrow therapeutic index drugs.