CRYSTAL PACKING EFFECTS ON THE PHOTOCHEMICAL OXIDATION AND SOLID STATE CARBON-13 NMR CHEMICAL SHIFTS OF SEVERAL ANTI-INFLAMMATORY STEROIDS (POLYMORPHISM, CONFORMATION, STABILITY)
Abstract
The crystal structure was determined for five prednisolone 21-tert-butylacetate (PTBA) crystal forms, two prednisolone crystal forms, one cortisol crystal form, two fluprednisolone crystal forms, two 9(alpha)-fluorocortisol acetate crystal forms, one cortisol acetate crystal form and one cortisol 17, 20(beta)-acetonide acetate (CAA). Conformational analysis of these structures showed some unusual variations. Cortisol acetate and 9(alpha)-fluorocortisol acetate (II) both showed an inverted A-ring. The bowing of the steroid nucleus showed some large variations between crystal forms and structurally similar steroids. The crystal structure data were used to determine which factors influenced solid state C-13 NMR chemical shifts most significantly. Among the factors examined were conformation, crystal packing and hydrogen bonding. The C(9) carbon showed significant (> 5 ppm) chemical shift variation between steroids with the normal versus inverted A-ring. This change was attributed to the conformational variations at the C(1)-C(10) bond. Intermolecular shielding could account for shift variations of up to 4 ppm. Hydrogen bonding had the greatest influence on chemical shift variation, accounting for variations of up to 11 ppm. Hydrogen bonding influenced the chemical shifts of carbonyl carbons and carbons conjugated with a carbonyl group exclusively. PTBA (V) and CAA are both sensitive to oxidation at the 0(11) position in the presence of light and air. The crystal packing of PTBA(V) shows channels which can allow penetration of oxygen into the crystal lattice. CAA does not have any channels in its crystal packing and therefore its oxygen sensitivity is probably a surface phenomenon. Of twenty-one crystal forms studied, three were found to be sensitive to oxidation.
Degree
Ph.D.
Subject Area
Analytical chemistry
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