POLYMORPHS OF HYDROCORTISONE 21-ESTERS: THEIR CHARACTERIZATION AND SOLID-STATE REACTIVITY (ANTIINFLAMMATORY, X-RAY CRYSTALLOGRAPHY, OXIDATION)
Abstract
Several hydrocortisone-21-esters have been synthesized, the 3-,4-,5-, and 6-carbon esters and the 3-cyclopentyl-1-oxopropionate ester. They have been crystallized in different crystal forms and structurally characterized using X-ray crystallography. Several of these hydrocortisone-21-esters have been found to be sensitive to heat and UV light, resulting in the oxidation of the 11(beta)-OH to an 11-ketone. The X-ray crystallographic studies in our laboratories have shown that this oxidation of the hydrocortisone-21-esters is specific for only the hexagonal crystal form. The oxidation process has been shown to need molecular oxygen, and follows a free radical mechanism. All hexagonal crystal forms reveal a tunnel down the center of the unit cell along the c-axis with cross sectional area ranging from 25 to 33 (ANGSTROM)('2). This evidence strongly suggests that molecular oxygen can readily pass into the unit cell, come in contact with the 11(beta)-OH, and cause it to be oxidized to the 11-ketone. However, time dependent UV oxidation studies, along with HPLC analysis indicates that only surface oxidation is occurring. This has led us to believe that either, (a) the oxidation product is adopting a new crystal form, thereby blocking the tunnel leading into the unit cell; (b) solvent, which has been found in the tunnel of these hexagonal crystal forms, is blocking the penetration of molecular oxygen into the unit cell; or (c) a combination of both of these could be accounting for only surface oxidation. Solid state C-13 CP/MAS NMR of several of the hexagonal crystals reveals resonance peaks for ethanol, the solvent of crystallization. Both the methylene and methyl resonances survive 71 usec of interrupted decoupling, suggesting greater mobility. However, a static solid state spectrum shows no clear signals for ethanol, so the solvent does not appear to be liquid-like in its motion. From the thermal gravimetric analysis data, the ethanol does not evaporate out of the unit cell until 120(DEGREES)C, and upon doing so, changes the crystal form from hexagonal to orthorhombic. This data further supports that the solvent in the unit cell is not liquid-like, and therefore cannot readily diffuse from the tunnel. The investigation has been extended into the study of several steroid-21-esters that are on the market today. The crystal form(s) found in these products are determined and compared to the crystal forms found in our laboratories.
Degree
Ph.D.
Subject Area
Pharmacology
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