Mechanism of dehydration and hydration of tolmetin sodium dihydrate and its lithium and potassium salts

Rajendra Sadashiv Sathe, Purdue University

Abstract

The process of dehydration, and subsequent rehydration, of the hydrates of tolmetin lithium, sodium and potassium was evaluated. The rate of dehydration increased with an increase in temperature and the rate decreased with an increase in relative humidity. The heat of dehydration for the three hydrates, obtained by DSC analysis, were 2.63, 6.7 and 3.09 kcal/mol, respectively. The rate of hydration of anhydrous tolmetin sodium increased with increasing temperature and relative humidity. X-Ray single crystal analysis showed that there are tunnels in the crystals along the a and b axis directions for the hydrates of the three salts of tolmetin. Within each salt, the a and b dimensions were essentially equal. The widths of these tunnels were about 2.0, 2.75 and 3.25 Angstroms in tolmetin lithium dihydrate, tolmetin sodium dihydrate and tolmetin potassium 1.6 hydrate, respectively. The molecules of water of hydration were located in these tunnels and appeared to be associated with the tolmetin molecules by ion-dipole and hydrogen bonding forces. There were no such tunnels in anhydrous tolmetin sodium. The tunnels were absent in the c axis direction in all cases. Dehydration occurred by a two-dimensional diffusion process. The diffusion coefficients increased with increase in temperature and were in the order of $10\sp{-11}$ to $10\sp{-8}$ cm$\sp2$/sec from 50$\sp\circ$C to 80$\sp\circ$C. Energies of activation for diffusion were 14.50, 21.15 and 14.69 kcal/mol. for the hydrates of tolmetin lithium, sodium and potassium, respectively. Diffusion coefficients for the hydration process, based on a two-dimensional diffusion model, were in the order of $10\sp{-8}$ cm$\sp2$/sec. Unlike dehydration, the diffusion coefficients did not increase with temperature. X-Ray powder diffraction analysis of tolmetin sodium showed that the change in crystal structure from the dihydrate to the anhydrous form does not start to occur until about half the water of hydration (1 mole) is lost from the crystal. Similar analysis for the hydration of anhydrous tolmetin sodium showed that there was no such time lag and the crystal structure started to change from the anhydrous to the dihydrate as soon as the crystals were exposed to a high humidity environment.

Degree

Ph.D.

Advisors

Kildsig, Purdue University.

Subject Area

Pharmacology|Pharmaceuticals

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