Patent TW-201519892-A (TW)
Title: Crystals of laquinimod sodium and improved process for the manufacture thereof
Inventor: FRENKEL ANTON
IPC: A61K31/4704
Filed: 2014-03-14
Abstract: The subject invention provides a mixture of crystalline laquinimod sodium particles, wherein (i) 90% or more of the total amount by volume of the laquinimod sodium particles have a size of 40 microns or less or (ii) 50% or more of the total amount by volume of the laquinimod sodium particles have a size of 15 microns or less, and wherein: (a) the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL; (b) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL; (c) an amount of heavy metal in the mixture is no more than 0.002% of heavy metal relative to the amount by weight of laquinimod soditum; (d) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC; (e) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (MCQCA) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC; or (f) an amount of methyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (MCQME) in the mixture is no more than 0.12% relative to the amount of laquinimod sodium as measured by HPLC. The subject invention also provides a pharmaceutical composition comprising an amount of laquinimod and at least one of 2-chloro-6-(3-(ethyl(phenyl)amino)-2-hydroxy-N-methyl-3-oxopropanamido)benzoic acid (BH-3-HLAQ), 5-Chloro-4-hydroxy-1-methylquinolin-2(1H)-one (MCQ), 5-Chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (MCQCA), Methyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (MCQME), N-Ethylaniline (NEA), and Ethyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (MCQEE). The subject invention also provides processes for preparing BH-3-HLAQ, MCQ, MCQCA, MCQME, MCQEE, and compounds prepared by said processes. The subject invention also provides a process for testing whether a sample of laquinimod contains an undesirable impurity. The subject invention further provides a process for preparing a validated pharmaceutical composition comprising laquinimod, a process for preparing a pharmaceutical composition comprising laquinimod, or for distributing a validated batch of a pharmaceutical composition comprising laquinimod, a process for validating a batch of a pharmaceutical product containing laquinimod or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for distribution, and a process for preparing a packaged pharmaceutical composition comprising laquinimod or a pharmaceutically acceptable salt thereof, each comprising determining the amount of at least one of BH-3-HLAQ, MCQ, MCQCA, MCQME, NEA, and MCQEE in a sample or batch. The subject invention further provides use of BH-3-HLAQ, MCQ, MCQCA, MCQME, MCQEE as a reference standard to detect trace amounts of the impurity in a pharmaceutical composition comprising laquinimod. Finally, the subject invention provides methods of determining the concentration of BH-3-HLAQ, MCQ, MCQCA, MCQME, MCQEE, 5-HLAQ, SPIRO-LAQ or 3 H-LAQ in a pharmaceutical composition comprising laquinimod.