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PROCESS FOR PREPARATION OF AMORPHOUS OLANZAPINE

IP.com Disclosure Number: IPCOM000145616D
Publication Date: 2007-Jan-19
Document File: 7 page(s) / 114K

Publishing Venue

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Abstract

Processes for the preparation of amorphous olanzapine which is amenable to commercial scale handling have been described.

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PROCESS FOR PREPARATION OF AMORPHOUS OLANZAPINE

Bhargav Pandya, Satish Kumar, Ramnik Sharma, Kamal Mehta, Rajeev Shanker Mathur, and Ram Chander Aryan

Ranbaxy Laboratories Limited, Plot 20, Sector 18, Udyog Vihar, Gurgaon -122001, Haryana, India

Abstract

            Processes for the preparation of amorphous olanzapine which is amenable to commercial scale handling have been described.

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2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine; commonly known as olanzapine of Formula I is a psychotropic agent that belongs to the thienobenzodiazepine class. Olanzapine is indicated for the treatment of schizophrenia, acute mixed or manic episodes associated with Bipolar I Disorder. In combination with lithium or valproate olanzapine is indicated for the short-term treatment of acute manic episodes associated with Bipolar I Disorder.

Amorphous form of olanzapine is well known in literature. However, the available processes are not conducive to large scale production and handling. They also do not give a product that is consistently amorphous. From a regulatory perspective, it is important to have material that is consistent in its physico-chemical characteristics. That could only be achieved by a process that can reproducibly deliver such product. At the same time, the process also needs to be commercially viable. The authors have developed two such processes for preparing amorphous olanzapine which makes isolation of the amorphous product amenable to commercial scale handling.

The first process involves

a)                  treating olanzapine in a suitable solvent,

b)                  adding a second solvent to the solution from stage (a) or adding solution from stage (a) to a second solvent in order to precipitate olanzapine, and

c)                  isolating the amorphous olanzapine.

In stage (a), olanzapine is treated with a suitable solvent selected from a group comprising water, lower alkanols, esters, ethers, ketones, hydrocarbons, polar aprotic solvents or mixtures thereof and to the solution a second solvent selected from a group comprising lower alkanols, esters, ethers, ketones, hydrocarbons, polar aprotic solvents or mixtures thereof in optional order of succession, is added to effect the precipitation of olanzapine. The lower alkanol is selected from the group comprising methanol, ethanol, isopropanol and n-propanol. The esters are selected from the group comprising ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, butyl acetate and amyl acetate. The ether is selected from the group comprising tetrahydrofuran, 1,4-dioxane. The ketone is selected from the group comprising acetone, ethyl methyl ketone, methyl isobutyl ketone and diisobutyl ketone. The hydrocarbon is selected from the group...