Synthesis and characterization of impurities of an anti-psychotic drug substance, Olanzapine

Poornachander Thatipalli; Ramesh Kumar; Chandrasekhar Bulusu; Ramesh Chakka; Pratap R. Padi; Anjaneyulu Yerra; Satyanarayana Bollikonda

doi:10.3998/ark.5550190.0009.b19

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Synthesis and characterization of impurities of an anti-psychotic drug substance, Olanzapine

Poornachander Thatipalli; Ramesh Kumar; Chandrasekhar Bulusu; Ramesh Chakka; Pratap R. Padi; Anjaneyulu Yerra; Satyanarayana Bollikonda

Volume 2008, Issue 11, pp. 195-201

DOI: http://dx.doi.org/10.3998/ark.5550190.0009.b19

Paper ID: 08-3022UP

Received on 2008-01-28; Accepted on 2008-03-23; Published on 2008-04-04

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General Papers ARKIVOC 2008 (xi) 195-201 Synthesis and characterization of impurities of an anti-psychotic drug substance, Olanzapine Poornachander Thatipalli,a Ramesh Kumar,a Chandrasekhar Bulusu,a Ramesh Chakka,a Pratap R. Padi,a Anjaneyulu Yerra,b and Satyanarayana Bollikondaa,* aDr Reddy’s Laboratories Limited, Bachupalli, Qutubullapur, Rangareddy District-72, Andhra Pradesh, India. Fax: 91 40 4434 6285 bInstitute of Science and Technology, JNTU, Hyderabad. IPDO-IPM Communication No.00097 E-mail: [email protected] Abstract HPLC analysis of olanzapine 1, a known anti-psychotic drug, showed impurity peaks ranging from 0.05 to 0.15 % during process development. These samples were analyzed by LCMS and the peaks were identified at m/z 230, 341, 511, 326, 361 and 329. All six impurities were synthesized individually and characterized based on their spectral data (IR, NMR and Mass). The structure of these impurities were assigned as 2-methyl-4,9-dihydro-3-thia-4,9diazabenzo[ f]azulen-10-one 4, 1-[4-(2-methyl-4H-3-thia-4,9-diazabenzo[f]azulen-10-yl) piperazin-1-yl]ethanone 5, bis-[10-(2-methyl-4H-3-thia-4,9-diazabenzo[f]azulene)]-1,4piperazine 6, 2,4-dimethyl-10-(4-methylpiperazin-1-yl)-4H-3-thia-4,9-diazabenzo[f]azulene 7, 10-(4-chloromethyl-4-methylpiperazin-1-ylium)-2-methyl-4H-3-thia-4,9-diazabenzo[f]azulene chloride 8 and 2-methyl-10-(4-methyl-N-oxopiperazin-1-yl)-4H-3-thia-4,9-diazabenzo[f]azulene 9 respectively. The formation, synthesis and characterisation of the olanzapine impurities are discussed. Keywords: Olanzapine, impurity profile, related substances Introduction Olanzapine 1, an atypical anti-psychotic drug1,2 with a thienobenzodiazepinyl structure, is indicated for the treatment of schizophrenia. It displays a broad pharmacological profile and is a selective monoaminergic antagonist with high affinity binding to serotonin 5HT2A/2C, dopamine D14, muscrinic M1-5 and adrenergic a1 receptors3,4,5. The HPLC analysis of olanzapine displayed six impurity peaks in the range of 0.05 to 0.15% levels along with the olanzapine peak. As per the guidelines recommended by ICH, the acceptable level for a known or unknown related compound (impurity) is less than 0.15 and 0.10 ISSN 1551-7012 Page 195 ©ARKAT USA, Inc.