Research On Purification And Quality Control Of Olanzapine Bulk

Olanzapine(OLA), whose trade name is Zyprexa, was developed by the United State Eli Lilly and Company and approved for marketing by USFDA in1996. It is a kind of5-serotonin and dopamine dual receptor antagonist for the treatment of positive and negative symptoms of schizophrenia and cognitive dysfunction. OLA is a new type of atypical anti-psychotics widely used clinically for its high security and small side effects. OLA belonged to a blockbuster drugs in the world when Zyprexa sales of Eli Lilly and Company were$5.03billion in2010. Compound patents expired in April2011.This paper used a composite solvent recrystallization method of once ethanol and twice ethyl acetate to purify OLA raw material and adopted the United States pharmacopoeia34version high performance liquid chromatography method of testing with the individual impu-rity content was less than0.1%and the total impurity content were less than0.4%, that reached the United States pharmacopoeia34version standard. Recrystallization product yield from ethanol was96%, twice recrystallization product yield from ethyl acetate were63%and68%separately and OLA final product yield was41%. The X-ray powder diffraction analysis data of OLA raw materials after composite solvent recrystallization was consistent with Zyprexa crystal shape I, and then the crystal structure was verified.Destructive testing for OLA raw materials after composite solvent recrystallization was performed in the condition of acid, alkali, oxidation, light and high temperature, which proved the feasibility of United States pharmacopoeia34version high performance liquid chroma-tography method. The stability of OLA was also studied to be placed in accelerated test chamber of40℃±2℃in temperature and75%±5%in humidity, and long-time test chamber of25℃±2℃in temperature and60%±5%in humidity. As a result, the samples did not changed significantly, the related substance content meet the requirements.OLA raw materials took place light reaction in the solvent of methylene chloride with tetraphenyl porphyrin as photosensitizer and azodiisobutyronitrile as free radical initiator, and the OLA related substances were separated by silica gel column chromatography and reverse preparation liquid phase.4-(4-methyl-piperazin-1-y1)-3-(2-oxo-propylidene)-1,3-dihydro-benzo[b][1,4]diazepin-2-one and1-[4-(4-methyl-piperazin-1-y1)-2-thioxo-1,2-dihydro-benzo [b][1,4]diazepin-3-ylidene]-propan-2-one.