WO2006030300A2

WO2006030300A2 - Processes for the preparation of olanzapine

Info

Publication number: WO2006030300A2
Application number: PCT/IB2005/002749
Authority: WO
Inventors: Bhargav R. Pandya; Ram Chander Aryan; Yatendra Kumar
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2004-09-17
Filing date: 2005-09-16
Publication date: 2006-03-23
Anticipated expiration: 2007-03-17
Also published as: WO2006030300A3

Abstract

The invention relates to processes for the preparation of a crystalline polymorphic form of olanzapine. More particularly, it relates to the preparation of a crystalline polymorphic form of olanzapine designated as Form X and to pharmaceutical compositions that include the polymorphic Form X. The invention also relates to a process for the preparation of a methanol solvate of olanzapine and a process for using such solvate.

Description

PROCESSES FOR THE PREPARATION OF OLANZAPINE

Field of the Invention

The field of the invention relates to processes for the preparation of a crystalline polymorphic form of olanzapine. More particularly, it relates to the preparation of a crystalline polymorphic form of olanzapine designated as Form X and to pharmaceutical compositions that include the polymorphic Form X. The invention also relates to a process for the preparation of a methanol solvate of olanzapine and a process for using such solvate.

Background of the Invention

Chemically, olanzapine is 2-methyl-4-(4-methylpiperazin-l-yl)-10H-thieno[2,3- Z>][l,5]benzodiazepine having the structural Formula I. It 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. It is indicated for the short- term treatment of acute manic episodes associated with Bipolar I Disorder in combination with lithium or valproate.

FORMULA I

United States Patent No. 5,736,541 discloses Form II of olanzapine having a specific X-Ray diffraction pattern. It further discloses that the material produced using the methods described in United States Patent No. 5,229,382 is Form I of olanzapine. Form I has been found to be metastable and not well suited for commercial use in pharmaceutical formulations. It also discloses that Form II is rather difficult to prepare in substantially pure form unless olanzapine of reasonable purity is used.

Several processes have been reported for the preparation of various hydrated and solvated polymorphic forms of olanzapine. For example, United States Patent No. 5,637,584 discloses mono-solvate of dichloromethane of olanzapine; United States Patent No. 6,020,487 discloses dihydrate Forms B, D and E of olanzapine; United States Patent No. 6,348,458 discloses Form III, IV and V of olanzapine; International (PCT) Publication No. WO 02/18390 discloses monohydrate-I and dihydrate-I of olanzapine; International (PCT) Publication No. WO 04/58773 discloses several polymorphic forms of olanzapine referred to as Form G, H, J, K, S, Q, X, Y and Z.

United States Application Publication No. 2002/0086993 discloses a process for the preparation of Form X of olanzapine. The process involves dissolving olanzapine in a mixture of acetone or methyl isobutyl ketone and water followed by evaporating the solvent at room temperature by exposing the solution to atmosphere till a specific quantity of mixture remains in the container. Form X of olanzapine is then isolated from the reaction mass by filtration. The yield of Form X from olanzapine is reported to be about 25 to 50%.

United States Patent No. 5,703,232 discloses solvates of anhydrous olanzapine with methanol, ethanol and isopropanol. The methanol solvate of olanzapine is prepared by two processes. The crude olanzapine in 8:2 mixtures of ethyl acetate and methanol is placed in a glass vial. The vial and contents, in turn are placed inside a larger vial containing silicone oil. The outer vial is sealed and the contents are allowed to stand undisturbed at ambient temperature for about 10 days to get the methanol solvate. In another process, the crude olanzapine is heated to 78⁰C with 1 : 1 mixture of methanol and water followed by cooling to get the methanol solvate of olanzapine. Description of the Drawings

Figure 1 is an X-ray powder diffraction pattern of Form X of olanzapine.

Figure 2 is an infrared spectrum of Form X of olanzapine.

Figure 3 is an X-ray powder diffraction pattern of methanol solvate of olanzapine. Figure 4 is an infrared spectrum of methanol solvate of olanzapine.

Summary of the Invention

In one general aspect there is provided a process for the preparation of Form X of olanzapine. The process includes obtaining a solution of olanzapine in one or more organic solvents; adding an aqueous solution of an inorganic salt to the solution; and isolating the Form X of olanzapine.

Isolating may include, for example, one or more of filtration, filtration under vacuum, decantation and centrifugation. The process may include further forming of the product so obtained into a finished dosage form. The process may include further drying of the product obtained.

In another general aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of the Form X of olanzapine; and one or more pharmaceutically acceptable carriers, excipients or diluents.

In another general aspect there is provided a method for treating schizophrenia, acute mixed or manic episodes associated with Bipolar I Disorder in a warm-blooded animal. The method includes providing a pharmaceutical composition to the warm-blooded animal, the pharmaceutical composition comprising Form X of olanzapine.

In another general aspect there is provided a process for the preparation of methanol solvate of olanzapine. The process includes obtaining a solution of olanzapine in one or more organic solvents; adding methanol to the solution; and isolating the methanol solvate of olanzapine.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description, figures, and claims. Detailed Description of the Invention

The inventors have developed a process for the preparation of a crystalline polymorphic Form X of olanzapine. The process is simple, cost-effective and involves less use of organic solvents. The inventors have also developed a process for the preparation of methanol solvate of olanzapine which does not involve heating and cooling cycles. The process is simple, and commercially scalable.

The term "Form X" of olanzapine refers to a polymorph of olanzapine having X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 1. The "methanol solvate" of olanzapine has X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 3.

A first aspect of the present invention provides a process for the preparation of Form X of olanzapine wherein the process includes the steps of: a) obtaining a solution of olanzapine in one or more organic solvents; b) adding an aqueous solution of an inorganic salt; and c) isolating the Form X of olanzapine.

In general, the solution of olanzapine may be obtained by dissolving olanzapine in a suitable solvent. Alternatively, such a solution may be obtained directly from a reaction in which olanzapine is formed. If a suspension is obtained in a solvent, the suspension containing olanzapine may be heated to obtain a solution. It may be heated from about 30⁰C to about 150⁰C, for example from about 50⁰C to about 100⁰C. It may be heated from about 10 minutes to about 24 hours

The olanzapine can be prepared by any of the methods known in the art including those described in United States Patent Nos. 5,736,541; 5,229,382; 6,348,458; WO 04/58773; and U.S. Application No. 20020086993.

The term "olanzapine" includes all polymorphic forms, amorphous form, solvates, hydrates, and mixtures thereof.

The olanzapine which is used as the starting material can be pure or crude existing in any polymorphic forms mentioned earlier. The term "suitable solvents" includes any solvent or solvent mixture in which olanzapine can be solubilized, including, for example, ketones, lower alkanols, or mixtures thereof. The ketones may include one or more of acetone, ethyl methyl ketone, methyl isobutyl ketone, diisobutyl ketone, methyl t-butyl ketone and cyclohexanone. Examples of alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable lower alkanol solvents include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol and t-butanol. Mixtures of all of these solvents are also contemplated. An aqueous solution of an inorganic salt may be added in a quantity sufficient to induce crystallization. The inorganic salt may include one or more of water soluble sodium, calcium or potassium salts for example, sodium chloride, potassium chloride, calcium chloride, and the like. The resultant mass may be stirred from ambient temperature to about O⁰C for a time sufficient to complete crystallization. The separated crystals may be removed from the solution by a technique which includes, for example, filtration, filtration under vacuum, decantation and centrifugation. The product may be washed and dried by conventional methods to get the Form X of olanzapine.

The Form X of olanzapine may have the X-ray diffraction pattern of Figure 1, and infrared spectrum of Figure 2. A second aspect of the present invention provides a process for the preparation of methanol solvate of olanzapine wherein the process includes the steps of: a) obtaining a solution of olanzapine in one or more organic solvents; b) adding methanol to the solution; and c) isolating the methanol solvate of olanzapine. hi general, the solution of olanzapine may be obtained by dissolving olanzapine in a suitable solvent. Alternatively, such a solution may be obtained directly from a reaction in which olanzapine is formed. The solvent containing olanzapine may be heated to obtain a solution.

The olanzapine which is used as the starting material can be pure or crude existing in any polymorphic forms mentioned earlier.

The term "suitable solvents" includes any solvent or solvent mixture in which olanzapine can be solubilized, including, for example, ketones, or mixtures thereof. The ketones may include one or more of acetone, ethyl methyl ketone, methyl isobutyl ketone, diisobutyl ketone, methyl t-butyl ketone and cyclohexanone. Mixtures of all of these solvents are also contemplated.

Methanol may be added in a quantity sufficient to induce crystallization. The resultant mass may be stirred from ambient temperature to about O⁰C for a time sufficient to complete crystallization. The separated crystals may be removed from the solution by a technique which includes, for example, filtration, filtration under vacuum, decantation and centrifugation. The product may be washed and dried by conventional methods to get the methanol solvate of olanzapine. The methanol solvate may have the X-ray diffraction pattern of Figure 3, and infrared spectrum of Figure 4. In another aspect, the methanol solvate of olanzapine may be converted to olanzapine by drying under vacuum at a temperature from about 4O⁰C or more.

The resulting polymorphic forms of olanzapine may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. In these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.

The compositions include dosage forms suitable for oral, buccal, rectal, and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration. The oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions, emulsions, pastes and elixirs. Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.

The polymorphic forms of olanzapine can be administered for the treatment of schizophrenia, acute mixed or manic episodes associated with Bipolar I Disorder in a warm- blooded animal.

For the purpose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1: Preparation of Form X of olanzapine Olanzapine (2 gm) was dissolved in acetone (35 ml) at 25 to 3O⁰C. The solution was stirred and an aqueous sodium chloride solution (75 ml, 20%) was added at about 25-3O⁰C. The resultant mass was further stirred for one hour at ambient temperature and was filtered. The product was dried at ambient temperature to get Form X of olanzapine.

Yield: 2.0 g Example 2: Preparation of Form X of olanzapine

Olanzapine (1 gm) was dissolved in acetone (25 ml) and methanol (10 ml) at 25 to 3O⁰C. The solution was stirred and an aqueous sodium chloride solution (75 ml, 20%) was added at about 5⁰C. The resultant mass was further stirred for one hour at 5⁰C and was filtered. The product was dried at ambient temperature to get Form X of olanzapine. Yield: 1.0 g

Example 3: Preparation of methanol solvate of olanzapine

Olanzapine (1 gm) was dissolved in acetone (5 ml) at 25 to 3O⁰C. The solution was stirred and methanol (10 ml) was added at about 15⁰C. The resultant mass was further stirred for one hour at ambient temperature and was filtered. The product was dried in an oven at ambient temperature to get methanol solvate of olanzapine.

Yield: 0.85 g

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. For example, it is understood that the various polymorphic forms of olanzapine can be incorporated in dosage forms for treating conditions for which olanzapine is useful.

Claims

We Claim: 1. A process for the preparation of Form X of olanzapine, the process comprising: a) obtaining a solution of olanzapine in one or more organic solvents; b) adding an aqueous solution of an inorganic salt; and c) isolating the Form X of olanzapine. 2. The process of claim 1, wherein the organic solvent comprises one or more of ketones, lower alkanols, or mixtures thereof. 3. The process of claim 2, wherein the ketone comprises one or more of acetone, ethyl methyl ketone, methyl isobutyl ketone, diisobutyl ketone, methyl t-butyl ketone and cyclohexanone. 4. The process of claim 2, wherein the lower alkanol comprises one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and t-butanol. 5. The process of claim 1, wherein the inorganic salt comprises one or more of water soluble sodium, potassium, or calcium salts. 6. The process of claim 5, wherein the inorganic salt is sodium chloride, potassium chloride, or calcium chloride. 7. The process of claim 1, wherein the isolating comprises one or more of filtration, filtration under vacuum, decantation and centrifugation. 8. The process of claim 1, further comprising additional drying of the product obtained. 9. The process of claim 1, wherein the Form X of olanzapine has the X-ray diffraction pattern of Figure 1 and infrared spectrum of Figure 2. 10. The process of claim 1, further comprising forming the product into a finished dosage form. 11. A method of treating schizophrenia, acute mixed or manic episodes associated with Bipolar I Disorder, the method comprising providing a pharmaceutical composition to the warm-blooded animal that includes Form X of olanzapine prepared by the process of claim 1. 12. A process for the preparation of methanol solvate of olanzapine, the process comprising: a) obtaining a solution of olanzapine in one or more organic solvents; b) adding methanol to the solution; and c) isolating the methanol solvate of olanzapine. 13. The process of claim 12, wherein the organic solvent comprises one or more of ketones, or mixtures thereof. 14. The process of claim 13, wherein the ketone comprises one or more of acetone, ethyl methyl ketone, methyl isobutyl ketone, diisobutyl ketone, methyl t-butyl ketone and cyclohexanone. 15. The process of claim 12, wherein the isolating comprises one or more of filtration, filtration under vacuum, decantation and centrifugation. 16. The process of claim 12, further comprising additional drying of the product obtained. 17. The process of claim 12, the methanol solvate of olanzapine has the X-ray diffraction pattern of Figure 3 and infrared spectrum of Figure 4. 18. The process of claim 12, further comprising converting the methanol solvate of olanzapine into olanzapine.