The solid state reactivity of the crystal forms of hydrocortisone esters

Abstract

The crystal structure of the hexagonal and orthorhombic crystal forms of 21-oxobutoxy-11β,17α-dihydroxypregn-4-ene-3,20-dione, the orthorhombic crystal form of 21-oxopropoxy-11β,17α-dihydroxypregn-4-ene-3, 20-dione and the hexagonal forms of 21-oxopentoxy-, 21-oxocaproxy-, 21-(3-cyclopentyl-1-oxopropoxy)-, 9-α-fluoro-21-oxobutoxy, and 9-α-fluoro-21-oxopentoxy-11β, 17a-dihydroxypregn-4-ene-3, 20-dione were solved and refined. The A-ring is in the normal conformation (1α-2β-half chair) in all of the hexagonal crystal forms and in the inverted conformation in the two orthorhombic crystal forms. The hexagonal crystal forms tightly bind solvent in a ratio of about 1:2 solvent:steroid. They also react with oxygen in the presence of UV light to form the corresponding 11-ketone. The orthorhombic forms are not oxygen sensitive. The presence of the free radical scavenger BHT reduces the oxidation of the hexagonal forms. The extent of oxidation is related to surface area. One hypothesis explaining this behavior is that the solvent present in the crystal inhibits oxygen penetration. Preliminary solid state nmr studies of the thermal motion of the solvent indicate that it is not “liquid-like” in its behavior.