Triethylenetetramine is a polyamine type chelating ligand for copper (II), which is currently used, mainly in its dihydrochloride form, as an alternative to D-penicillamine against Wilson's disease. Because knowledge about the solid-state behavior of pharmaceuticals is a prerequisite for the development of an effective dosage form, the crystal structures of two triethylenetetramine dihydrochloride polymorphs have been determined and the infrared spectra and thermal expansion have been studied. No suitable crystals could be obtained of the two anhydrous forms, for which the structures have been solved from X-ray powder diffraction. Form I is monoclinic P21/n with the cell parameters a = 11.0475 (4)
The API triethylenetetramine dihydrochloride used as an alternative treatment of Wilson's disease is sensitive to water and it exhibits polymorphism. As this may become an issue for the drug formulation, the physical stability has been studied by differential scanning calorimetry, highpressure thermal analysis, dynamic vapor sorption, and X-ray diffraction as a function of temperature. In addition, high-pressure liquid chromatography and mass spectrometry have been used to study the purity and chemical stability of the API. A pressure-temperature phase diagram of the pure compound has been constructed and it can be concluded that form II is monotropic in relation to form I, which is the only stable solid. The solubilities of the different solid forms have been determined with the help of a temperature -composition phase diagram. The API is very soluble, at 20° C about 10 % of the saturated solution with respect to the dihydrate consists of API and the solubility of the pure form I is twice as high. Moreover, it has been shown that at 20 °C, a relative humidity above 40 % induces the formation of the dihydrate and at 70 % a saturated solution appears. At higher temperatures, the formation of the dihydrate appears at lower relative humidity values. A clear link has been established between the API's chemical stability, its physical stability and the relative humidity in the air. Humidity levels above 40 % are detrimental to the quality of the API.3
The stability behavior of an active pharmaceutical ingredient (API) is important for the development of a reliable drug formulation. Triethylenetetramine dihydrochloride is an API used as second-line treatment of Wilson's disease since the early 1980's. Nonetheless, a comprehensive understanding of its stability behavior is lacking. In this work, its stability has been determined both in the solid state and in aqueous solution, thus evaluating on the one hand the relative stability of polymorphs and hydrates and, on the other hand, the main decomposition products and their pathways.For the solid-state study, the API was exposed to several conditions involving temperature and moisture content. Thermal analysis and dynamic vapor sorption were used to obtain information about the physical stability. Liquid chromatography-tandem mass spectrometry (LC-MS) was used to study the chemical decomposition. In addition, solutions of the API in water were exposed to heat, acid, alkaline and oxidative conditions, so-called stress tests, followed by LC-MS measurements.Solid-state analyses demonstrated the existence of two polymorphs and a dihydrate, as had been reported previously [1,2]. The dimorphism was found to be monotropic under ordinary conditions using the results from the thermal analysis in combination with the Ostwald rule and the Le Chatelier principle; the commercial form was the most stable of the two forms. In addition, the relative-humidity domain in which the dihydrate is stable has been assessed.Two compounds derived from triethylenetetramine were identified by LC-MS after the stress tests in solution. These compounds are found in very low levels in native samples too and might therefore be degradation products as well as impurities caused by synthesis.
References
Tirofiban in aqueous solution mostly photodegrades through photosensitized oxidation reactions and the photoproducts formed are not structurally alerting for genotoxicity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.