PHOTOINSTABILITY OF SOME TYRPHOSTIN DRUGS - CHEMICAL CONSEQUENCES OF CRYSTALLINITY

Purpose. The purpose of this work was to study the photostability of t he antiproliferative tyrphostin drug compounds RG 13022(I) and RG 1462 0(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 isola ted chromatographically and their structures determined by spectroscop ic 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 indica tive of the crystal packing of their monomeric precursors. The photocy cloaddition product of RG 13022 possesses the head-to-tail linkage as expected from the head-to-tail packing of RG 13022 molecules in the cr ystal. The photocycloaddition product of RG 14620, however, was found to involve head-to-head linkage in agreement with the head-to-head cry stal packing of RG 14620. Conclusions. Drug compounds containing open chain olefinic double bonds could be sensitive to mild condition of li ght in the solid state if the distance between the two double bonds in the crystal approaches 4.2 degrees A and they have suitable UV absorp tion characteristics. Attractive interactions between chlorine atoms h ave significant influence in controlling the crystal packing of chlori nated aromatic compounds.