Interactions between Drug Substances and Excipients. 1. Fluorescence and HPLC Studies of Triazolophthalazine Derivatives from Hydralazine Hydrochloride and Starch††Presented at the PharmAnalysis Conference ’95, Atlantic City, NJ, June 1995

Abstract

The strength of hydralazine hydrochloride (I) 10 mg tablets, containing starch as an excipient, decreases significantly with time. An investigation to determine the basis for the drop in strength showed that starch exposed to the drug exhibited fluorescence at 414 nm. As model compounds IIIa and V, which contain a triazolophthalazinyl moiety, also fluoresce at about 414 nm, it is proposed that the emission is due to a triazolophthalazine derivative (IIIc) resulting from hydralazine hydrochloride and starch. Degradation of IIIc generates s-triazolo[3,4-a]phthalazine (IIIb), and a small amount of IIIb is detected in aged tablets. IIIc in aged tablets can be converted to IIIb by acid-catalyzed hydrolysis. The quantity of IIIb determined by HPLC amounts to most of the "missing" hydralazine hydrochloride. The reaction between hydralazine hydrochloride and starch is believed to cause the unexpected drop in the strength of hydralazine hydrochloride tablets.

Excipient Stability in Oral Solid Dosage Forms: A Review

“…A significant drop in the efficacy of hydralazine hydrochloride (HCl) has been reported during a routine shelf life study of hydralazine HCl tablets, which has been attributed to the reaction between hydralazine HCl and starch. The terminal glucose units in the starch molecule contain an aldehyde group in equilibrium with a cyclic hemiacetal, which reacts with the hydrazine moieties of hydralazine HCl and forms the degradation by-products, phthalazine hydrazone and triazolophthalazine derivatives [16]. In another study, trace amounts of formaldehyde generated by the hydrolysis of hydrochlorothiazide (HCTZ) from capsule formulations under high humidity conditions reacted with sodium starch glycolate (SSG), decreasing its functionality as a disintegrant and thus retarding the dissolution of the formulation [17].…”