Determination of the Degradation Chemistry of the Antitumor Agent Pemetrexed Disodium.
Stress-testing (forced degradation) studies have been conducted on pemetrexed disodium heptahydrate (1) (LY231514·2Na·7H2O) drug substance in order to identify its likely degradation products and establish its degradation pathways. Solid samples of the drug substance were stressed under various conditions of heat, humidity, and light, and solutions of the drug substance were stressed under various conditions of heat, light, oxidation, and over a wide pH range (1-13). The stressed samples were analyzed using a gradient elution reversed-phase HPLC method. The 7 major degradation products detected in the stress-testing studies were isolated, and the structures were elucidated via spectroscopic characterization. The structures of the degradation products and their proposed mechanisms of formation indicate that 1 degrades via 2 main pathways: oxidation and hydrolysis. Of the 7 identified degradation products, 6 are proposed to result from oxidation and 1 from hydrolysis.
Stress Testing: The Chemistry of Drug Degradation
In this chapter, we will examine the major mechanisms of chemical decomposition of pharmaceuticals in the context of common functional groups. The major mechanisms of chemical decomposition of pharmaceuticals include hydrolysis/dehydration, oxidation, isomerization/epimerization, decarboxylation, rearrangements, dimerization/polymerization, and photolysis and transformation products involving reaction with excipients/salt forms. In order to develop an understanding of the chemistry of such reactions, a basic knowledge of organic chemistry is needed. Providing such a background is not the purpose of this book, and therefore the reader may find it useful to
Rubik's for cryptographers
Hard mathematical problems are at the core of security arguments in cryptography. In this paper, we study mathematical generalizations of the famous Rubik’s cube puzzle, namely the factorization, representation and balance problems in non-Abelian groups. These problems arise naturally when describing the security of Cayley hash functions, a class of cryptographic hash functions with very interesting properties. The factorization problem is also strongly related to a famous long-standing conjecture of Babai, at the intersection of group theory and graph theory. A constructive proof of Babai’s conjecture would make all Cayley hash functions insecure, but on the other hand it would have many positive applications in graph theory and computer science. In this paper, we classify existing attacks against Cayley hash functions and we review known results on Babai’s conjecture. Despite recent cryptanalytic progress on particular instances, we show that the factorization, representation and balance problems presumably remain good sources of cryptographic hard problems. Our study demonstrates that Cayley hash functions deserve further interest by the cryptography community.