WO2007144901A1

WO2007144901A1 - Process for stabilization of olanzapine polymorphic form i

Info

Publication number: WO2007144901A1
Application number: PCT/IN2007/000233
Authority: WO
Inventors: Namdev Kashid; Gour Mukherji
Original assignee: Jubilant Organosys Limited
Priority date: 2006-06-12
Filing date: 2007-06-12
Publication date: 2007-12-21

Abstract

Disclosed herein a process for stabilization of polymorphic Form I of olanzapine. Said process comprises of micronizing said olanzapine in a fluid energy mill employing nitrogen or carbon dioxide.

Description

PROCESS FOR STABILIZATION OF OLANZAPINE POL YMORHPIC

FORM l

Field of the Invention In general, the present invention relates to a process for stabilization of polymorphic Form I of olanzapine. More particularly, the present invention provides a process employing fluid] energy mill to produce stable Form I of olanzapine.

Background of the Invention For poorly soluble drugs, the digestive absorption depends on their rate of dissolution. i Decreasing the particle size of these drugs improves their rate of dissolution. Fine grinding mills are used to micronize powders: either jet mills or fluid energy mills. These processes were applied to griseofulvin, progesterone, spironolactone and diosmin. For each drug, micronization improved their digestive absorption, and consequently their bioavailability and clinical efficacy.

Drugs which form crystalline solids often exists in more than one crystal form, each of which may have distinct properties in terms of solubility, melting point etc. Invariably, one of the crystal forms may be more stable or easier to handle than another. In some cases, one crystal form can be transformed into another during storage or while | processing of the drug for making physical formulations like tablet or capsules. The conversion of one polymorphic form of drug into another can also create differences in the bioavailabilty of drug, which may lead to inconsistencies in efficacy. Besides, polymorphic forms of the drugs can have pronounced effect on the legality of the generic formulations.

Olanzapine is a! psychotropic agent that belongs to the thienobenzodiazepine class. Olanzapine is yellow crystalline solid, which is practically insoluble in water leading to poor absorption and bioavailability problems. As described in US Patent Number 5,736,541 (hereinafter "the '541 patent"), the synthesis of olanzapine according to the methods described in US Patent Number 5,229,382 produces a metastable, dull colored product referred to in the '541 patent as "Form I." The '541 patent is herein incorporated by reference in its entirety. The '541 patent discloses and claims a more stable polymorphic form of olanzapine, designated as "Form II", a method to produce "Form II" olanzapine, and pharmaceutical compositions containing "Form II" olanzapine. "Form I" and "Form II" olanzapine are characterized in the '541 patent by powder X-ray diffraction. The interplanar spacings (d-spacings) and typical relative intensities (I/I.sub.l) are reported. The '541 patent also disclosed that Form I, is metastable and therefore not well suited for commercial use in pharmaceutical formulations. It has also been found that the micronization of olanzapine using high speed running mill leads to change in its Form I to Form II due to heat generation during the micronization process. Olanzapine is a poorly soluble drug at physiological conditions; therefore, micronization of olanzapine is one of the essential processes for conversion of the drug to suitable particle size having improved dissolution. Hence there is a need for a process to stabilize the polymorphic form of drugs like olanzapine especially during the micronization of the drugs.

It has been also been reported that olanzapine is sensitive to light and heat and tend to change its color on tablet processing.

Therefore, by the aforementioned facts there exists a necessity for a process to provide stable form I of Olanzapine along with desired bioavailability. Accordingly, the present invention provides a process for stabilization of form I of olanzapine, which obviates the drawbacks associated with prior arts.

Summary of the Invention It is a principal object of the present invention to provide a process for stabilization of polymorphic Form I of olanzapine, ensuring the stability of said Form I during and after the process.

Further object of the present invention is to provide a process for stabilization of polymorphic Form I of olanzapine, wherein said process avoids the conversion of Form I to Form II thereby achieving stable Form I of olanzapine, suited for commercial use in a preparation of pharmaceutical formulations. It is another object of the present invention to provide a process for stabilization of polymorphic Form I of olanzapine, wherein said process avoids the formation of degradation products thus ensuring the stability of said polymorph I along with enhanced dissolution of said form.

The above and other objects are achieved in accordance with following embodiments, however, the present invention is not limited to the preferred embodiments described herein below.

In accordance with one embodiment of the present invention, there is provided a process for stabilization of polymorphic Form I of olanzapine, wherein the process comprises of micronizing said olanzapine in a fluid energy mill employing a fluid to reduce heat generation, during the micronization process thereby producing stable polymorphic Form I of olanzapine with reduced side products.

In accordance with one embodiment of the present invention, there is provided a process for stabilization of polymorphic Form I of olanzapine, wherein the process comprises of micronizing said olanzapine in a fluid energy mill employing nitrogen or carbon dioxide as the operating fluid leads to stabilization of polymorphic Form I of olanzapine along with reduced level of side products.

Detailed Description of the Invention

While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of trie included examples.

\

The present invention describes a method of stabilization of polymorphic Form I of olanzapine by micronization of olanzapine Form I in fluid energy mill using nitrogen or carbon dioxide as the fluids for micronization. A fluid energy mill is a type of mill used to produce particles of small size in narrow size distribution. Fluid energy mill uses the kinetic energy of collision between particles suspended in a rapidly moving fluid (nitrogen, carbon dioxide) stream to cleave the particles. The suspended particles are injected under pressure into a recirculating particle stream. Smaller particles are carried aloft inside the mill and swept into a vent connected to a particle size classifier such as cyclone. The material is fed into the micronization system in a controlled feed rate by means of screw feeder or a vibratory feeder. The fluid energy mill is operated with controlled fluid pressures. Process parameters vary with the type and make of micronizer and type of material to be micronized.

For micronization carried out in Midas Mikronizer 50 Manufactured and supplied by Microtek Engineering Company, Thane, grinding nozzle pressure and pushing nozzle pressure is 4-6 kg/cm². The feed rate of the material to be micronized is 0.5 -1.5 g/minute and remains the same through out the entire process. Midas Mikronizer 50 has a grinding chamber of diameter of approximately 50mm. It has venturi based powder injection system for delivering the powder to the milling chamber.

The X-ray diffractogram clearly showed that olanzapine Form I is not changed to Form II after micronization. It maintains its initial polymorphic form.

The X-ray powder diffraction patterns of the micronized and unmicronized micronized olanzapine are obtained using Philips Expert 2.0 El, Model No: DYl 688 (X-ray Machine) manufactured and supplied by Philips India Limited, India

The average particle size of the micronized olanzapine polymorph Form I is below 20.5 μm. Preferably average particle size is below 11.3 μm. Average particle size is determined by Malvern method.

The following examples further illustrate the present invention. They are, however, not intended to be limiting the scope of the present invention in any way. V Example 1

Approximately 20 gram of olanzapine Form I (analyzed by X-ray pattern) was fed into fluid energy mill hopper with a feed rate of 1.5 gram per minute. Nitrogen was used as inert gas (fluid) during the milling operation. The grinding nozzle pressure and pushing nozzle pressure was maintained at 4-5 kg/cm . The X-ray powder diffraction patterns of the micronized olanzapine were obtained to establish the absence of any Form - II in the micronized powder of Form I. The micronization was carried out in Midas Mikronizer 50 manufactured and supplied by Microtek Engineering Company, Thane. The related substances in the micronized olanzapine Form I was analyzed using standard HPLC (high pressure liquid chromatography).

The results are compared with Form I of olanzapine used before the micronization. The results are tabulated in the table 1, IA, 2 and 2 A. Table 1 represents the X-ray powder diffraction pattern of Form I of olanzapine. Table IA represents x-ray powder diffraction patterns of Form II of olanzapine. Table 2 and table 2A represented the powder X-ray diffraction patterns of micronized olanzapine Form I and related substances of the micronized olanzapine respectively.

Table 1

Table 1 A

Table 2 A

From the above mentioned tabular data and its analysis, it is clearly evident that there is no conversion of Form I of olanzapine to Form II of olanzapine after fluid energy milling of olanzapine Form I and also there is no substantial increase in the level of the related substances after the fluid energy milling.

Example 2

The process is carried out as explained in example -1 with the exception that carbon dioxide was used in place of nitrogen as the fluid for the milling operation. Table 3 and table 3A represent the powder X-ray diffraction patterns of micronized olanzapine Form I and related substances of the micronized olanzapine respectively.

Table 3

Table 3A

While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations, would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

Claims

We claim:

1. A process for stabilization of polymorphic Form I of olanzapine comprising: micronizing said olanzapine Form I in a fluid energy mill, wherein said fluid energy mill employs nitrogen or carbon dioxide as the operating fluid.

2. The process according to claim 1, wherein the micronized olanzapine Form I is characterized by having pure and stable polymorphic Form I with substantially free of degradation products.

3. The process according to claim 1, wherein the micronized olanzapine Form I is characterized by having pure and stable polymorphic Form I with free of polymorphic Form II of olanzapine.

4. The process according to claim 1, wherein the micronization is carried out in Midas Mikronizer 50 having grinding nozzle pressure and pushing nozzle pressure maintained at 4-5 kg/cm².

5. The process according to claim 1, wherein said olanzapine Form I is fed into fluid energy mill hopper with a feed rate of 0.5- 1.5 g/minute.

6. The process according to claim 1 , wherein the micronization produces olanzapine Form I having average particle size is below 20.5μm.