Photoinstability of Some Tyrphostin Drugs: Chemical Consequences of Crystallinity

Abstract

Purpose. The purpose of this work was to study the photostability of the antiproliferative tyrphostin drug compounds RG 13022(I) and RG 14620(II) as a part of preformulation program.

Methods. The compounds were exposed to cool white fluorescent light in solution as well as in the solid state and analyzed by HPLC. The degradation products were isolated chromatographically and their structures determined by spectroscopic methods. X-ray crystallographic analyses of the above compounds and their solid state degradation products were carried out to understand the mechanism of photodegradation.

Results. The compounds were found to undergo efficient photochemical transformations in solution as well as in the solid state. The degradation in the solution was due to the photoisomerization into their E-isomers (III and IV). The solid state photodegradation products were [2 + 2]-cycloaddition products (V and VI). The stereochemistry of the photocycloaddition products was indicative of the crystal packing of their monomeric precursors. The photocycloaddition product of RG 13022 possesses the head-to-tail linkage as expected from the head-to-tail packing of RG 13022 molecules in the crystal. The photocycloaddition product of RG 14620, however, was found to involve head-to-head linkage in agreement with the head-to-head crystal packing of RG 14620.

Conclusions. Drug compounds containing open chain olefmic double bonds could be sensitive to mild condition of light in the solid state if the distance between the two double bonds in the crystal approaches 4.2°A and they have suitable UV absorption characteristics. Attractive interactions between chlorine atoms have significant influence in controlling the crystal packing of chlorinated aromatic compounds.