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.
A stability-indicating LC-MS/MS method optimization for Pemetrexed through design of experiments: Identification and characterization of major oxidative degradation product.
A stability-indicating high-performance liquid chromatography method for Pemetrexed bulk was developed and validated as per the ICH guidelines by employing design of experiments methodology equipped with Box-Behnken design. The separation of Pemetrexed and its oxidative degradation product was achieved in isocratic elution mode with Zorbax C18 column (150 mm x 4.6 mm x5 μm) using 10 mM ammonium acetate (pH 4.5 adjusted with acetic acid) and acetonitrile in the ratio of 50:50, v/v with a flow rate of 1.0 mL/min at detection wavelength of 223 nm. Tandem mass spectrometry method was adopted to identify and characterize the major oxidative degradation product. The results obtained indicate that the method is specific, linear, precise and accurate for the determination of Pemetrexed and characterization of degradation product.
How to do a p-descent on an elliptic curve
In this paper, we describe an algorithm that reduces the computation of the (full) p-Selmer group of an elliptic curve E over a number field to standard number field computations such as determining the (p-torsion of) the S-class group and a basis of the S-units modulo pth powers for a suitable set S of primes. In particular, we give a result reducing this set S of 'bad primes' to a very small set, which in many cases only contains the primes above p. As of today, this provides a feasible algorithm for performing a full 3-descent on an elliptic curve over Q, but the range of our algorithm will certainly be enlarged by future improvements in computational algebraic number theory. When the Galois module structure of E[p] is favorable, simplifications are possible and p-descents for larger p are accessible even today. To demonstrate how the method works, several worked examples are included.