WO2011033470A1

WO2011033470A1 - Crystalline form of montelukast sodium

Info

Publication number: WO2011033470A1
Application number: PCT/IB2010/054192
Authority: WO
Inventors: Shantanu De
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2009-09-16
Filing date: 2010-09-16
Publication date: 2011-03-24

Abstract

The present invention relates to a crystalline form of montelukast sodium. The crystalline form of montelukast sodium is designated as Form D1. The present invention also relates to a process for preparing crystalline montelukast sodium. The present invention further relates to a pharmaceutical composition comprising crystalline Form D1 of montelukast sodium and its method of use.

Description

CRYSTALLINE FORM OF MONTELUKAST SODIUM

Field of the Invention

The present invention relates to a crystalline form of montelukast sodium. The crystalline form of montelukast sodium is designated as Form Dl. The present invention also relates to a process for preparing crystalline montelukast sodium. The present invention further relates to a pharmaceutical composition comprising crystalline Form Dl of montelukast sodium and its method of use.

Background of the Invention

Montelukast Sodium is chemically [R-(E)]-l-[[[l-[3-[2-(7-chloro-2- quinolinyl)ethenyl] phenyl] -3- [2-(l -hydroxy - lmethylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt of Formula I:

FORMULA I

Montelukast sodium is an orally active, selective leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLTl receptor. It is commercially available for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older.

WO 95/18107 provides a process for the preparation of crystalline form A of montelukast sodium; wherein the process involves crystallization of montelukast sodium from an acetonitrile solvent system by seeding with crystalline montelukast sodium.

However, the method for preparing the seed crystals is not disclosed.

WO 2004/091618 states that contacting Form A of amorphous montelukast sodium, or a mixture thereof, with acetonitrile with little to no stirring or agitation provides montelukast sodium: acetonitrile monosolvate. WO 2004/091618 further states that when monosolvate is stirred or agitated in acetonitrile it is converted into montelukast sodium: acetonitrile hemisolvate, which is further converted into Form B of montelukast sodium on drying. Accordingly, Form A and Form B are considered desolvated forms.

WO 2005/075427 describes methods for the preparation of crystalline Form Al,

Form Bl, Form B2, Form C, Form D and Form E of montelukast sodium from amorphous montelukast sodium. The methods described involve dissolution of amorphous

montelukast sodium in a solvent and stirring until a precipitate is formed. The use of dimethyl carbonate provides Form Al; use of methyl isobutyl ketone provides Form Bl or Form B2 or a mixture of Form B2 with Form Bl or Form C; use of mixtures of dichloromethane and heptane provide Form Bl, Form C or Form D; dichloroethane provides Form C; use of a mixture of ethyl acetate and heptane provides Form B2 as wet material and Form Bl when dried; and use of butyl acetate provides Form E. The crystallizations are performed by stirring either at room temperature or at 55°C or 60°C. All these forms have been reported to have crystallinity index varying from 46% to 80%. However, WO 2005/075427 does not describe the details of the crystallization methods and states that crystallization may further include facilitative measures known to one skilled in the art. The facilitative measures include adding an agent to induce precipitation.

The method provided in WO 95/18107 for preparing Form A of

montelukast sodium results in amorphous or sticky material in the absence of the use of any seed crystal; for which no preparation method is disclosed. Thus, the preparation of Form B or acetonitrile solvates also becomes difficult in the absence of Form A as a starting material as per the methods described in WO 2004/091618. Further, reproducing the various crystalline forms described in WO 2005/075427 is also difficult in the absence of finer details of crystallization. In addition, the amorphous montelukast sodium does not go into solution state in many of the solvents or the volume of the solvents described.

While working on the problems associated with the prior art, the present inventors have found that amorphous montelukast sodium can be converted into a crystalline form, denoted as crystalline Form Dl of montelukast sodium, in a simple and reproducible manner without the use of any seeding. The crystalline form of the present invention does not convert into amorphous or any other form on further processing. Thus, the crystalline form of the present invention is suitable for preparing pharmaceutical dosage forms of montelukast sodium.

Summary of the Invention

In one general aspect, the present invention provides for crystalline Form Dl of montelukast sodium, which includes substantially the same XRPD pattern as depicted in Fig.l. The crystalline Form Dl of montelukast sodium has an XRPD pattern which includes interplanar spacing (d) values substantially 5.36, 5.22, 4.77, 4.18, and 4.07 (A). The crystalline Form Dl of montelukast sodium may further include interplanar spacing (d) values substantially at 23.60, 18.74, 14.51, 11.23, 9.33, 7.46, 5.61, 4.90, 4.41, 4.29, 3.83, 3.72, 3.42, and 3.19 (A).

In another general aspect, the present invention provides for a process for the preparation of crystalline Form Dl of montelukast sodium. The process includes:

a) treating amorphous montelukast sodium with dichloromethane and an

aliphatic hydrocarbon to obtain a mixture;

b) stirring or agitating the mixture obtained in step a) at a temperature of about

35°C to about 55°C; and

c) isolating crystalline Form Dl of montelukast sodium from the mixture thereof by filtration or decantation.

Embodiments of this aspect may include one or more of the following features. For example, the aliphatic hydrocarbon may be a C₅ to C₁₂ alkane or a mixture thereof. For example, the aliphatic hydrocarbon may be n-heptane, n-hexane or a mixture thereof.

The volume of the aliphatic hydrocarbon may be more than the volume of dichloromethane. The ratio of the volume of dichloromethane to the volume of aliphatic hydrocarbon is about 2:5. The combined volume of dichloromethane and aliphatic hydrocarbon is about 1.5 times to about 4 times more than the weight of amorphous montelukast sodium.

In another general aspect, the present invention provides for a pharmaceutical composition that includes crystalline Form Dl of montelukast and one or more

pharmaceutically acceptable excipients. In yet another aspect, the present invention provides for the use of crystalline Form Dl of montelukast sodium for the manufacture of a medicament for the prophylaxis or treatment of asthma in adults or pediatric patients.

Brief Description of the Drawings

Figure 1 depicts the X-ray powder diffraction pattern (XRPD) of crystalline Form

Dl of montelukast sodium.

Figure 1A: Table of values for the XRPD pattern depicted in Figure 1.

Detailed Description of the Invention

The present invention provides for a crystalline form of montelukast sodium, designated as Form Dl of montelukast sodium. The crystalline Form Dl of montelukast sodium has substantially the same XRPD pattern as depicted in Figure 1. The crystalline is characterized by an XRPD pattern that includes interplanar spacing (d) values

substantially at 5.36, 5.22, 4.77, 4.18, and 4.07 (A). Form Dl of montelukast sodium may also include interplanar spacing (d) values substantially at 23.60, 18.74, 14.51, 11.23, 9.33, 7.46, 5.61, , 4.90, , 4.41, 4.29, , 3.83, 3.72, 3.42, and 3.19 (A).

The present invention also provides for a process for the preparation of crystalline montelukast sodium. The process includes:

a) treating amorphous montelukast sodium with dichloromethane and an aliphatic hydrocarbon to obtain a mixture;

35°C to about 55°C; and

c) isolating crystalline montelukast sodium from the mixture thereof by filtration or decantation.

Amorphous montelukast sodium used as the starting material may be prepared according to the methods provided in, for example, WO 03/066598 and/or WO

2005/074893. Amorphous montelukast sodium is treated with a mixture of halogenated hydrocarbon and an aliphatic hydrocarbon. The aliphatic hydrocarbon may be a C₅ to C₁₂ alkane, for example, n-heptane or n-hexane, or a mixture thereof. The treatment with dichloromethane and the aliphatic hydrocarbon may be carried out by adding amorphous montelukast sodium to a mixture of dichloromethane and the aliphatic hydrocarbon or by adding a mixture of dichloromethane and the aliphatic hydrocarbon to amorphous montelukast sodium, or by adding dichloromethane and the aliphatic hydrocarbon to montelukast sodium in optional order of succession. Dichloromethane and the aliphatic hydrocarbon may be used in a ratio wherein the volume of the aliphatic hydrocarbon is more than that of dichloromethane; for example, the ratio of the volume of

dichloromethane to the volume of the aliphatic hydrocarbon is about 2:5. The combined volume of dichloromethane and the aliphatic hydrocarbon may be about 1.5 times to about 4 times more than the weight of amorphous montelukast sodium. For example, the combined volume of dichloromethane and the aliphatic hydrocarbon is about 1.5 ml to about 4 ml for about 1 g of amorphous montelukast sodium.

The mixture of amorphous montelukast sodium, dichloromethane and the aliphatic hydrocarbon are stirred or agitated at a temperature of about 35°C to about 55°C, for example, at about 50°C. The stirring or agitation may be carried out for a sufficient time to convert amorphous montelukast sodium into crystalline montelukast sodium. For example, the stirring or agitation may be carried out for about 5 hours to about 50 hours. After stirring or agitating at a temperature of about 35°C to about 55°C, the mixture may be cooled to about 20°C to about 25°C, and optionally further stirred for about 30 minutes to about 5 hours, for example about 1 hour. The crystalline montelukast sodium is isolated from the mixture by filtration or decantation. The crystalline montelukast sodium so obtained may be washed with an aliphatic hydrocarbon and dried. The crystalline montelukast sodium so obtained is crystalline Form Dl of montelukast sodium.

The present invention also provides a pharmaceutical composition that includes crystalline Form Dl of montelukast sodium and one or more pharmaceutically acceptable excipients.

Finally, the present invention provides for a method of treating leukotriene- mediated diseases. The method includes administering a patient in need thereof a therapeutically effective amount of crystalline Form Dl of montelukast sodium.

XRPD of the sample was determined by using Panalytical X'Pert Pro X-Ray Powder Diffractometer in the range 3-40 degree 2 theta and under tube voltage and current of 45 Kv and 40 mA respectively. Copper radiation of wavelength 1.54 angstrom and Xceletor detector was used.

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

Example 1: Preparation of Crystalline Form Dl of Montelukast Sodium

A mixture of dichloromethane and n-heptane (2:5, 13 ml) was added to amorphous montelukast sodium (5 g) at 20°C to 25°C. The mixture was heated to 50°C under stirring and the stirring was continued for 20 hours. The mixture was cooled to 20°C to 25°C and stirred for 1 hour. The suspended solid was filtered, washed with n-heptane (6 ml) and air dried for 12 hours to obtain the title product.

Yield: 2.5 g

Claims

We claim:

1. Crystalline Form Dl of montelukast sodium comprising substantially the same

XRPD pattern as depicted in Fig.l.

2. Crystalline Form Dl of montelukast sodium with an XRPD pattern comprising interplanar spacing (d) values substantially 5.36, 5.22, 4.77, 4.18, and 4.07 (A).

3. Crystalline Form Dl of montelukast sodium according to claim 2, further

comprising an XRPD pattern comprising interplanar spacing (d) values substantially at 23.60, 18.74, 14.51, 11.23, 9.33, 7.46, 5.61, 4.90, 4.41, 4.29, 3.83,

3.72, 3.42, and 3.19 (A).

4. A process for the preparation of crystalline Form Dl of montelukast sodium, wherein the process comprises:

35°C to about 55°C; and

5. A process according to claim 4, wherein the aliphatic hydrocarbon comprises a C₅ to Ci2 alkane or a mixture thereof.

6. A process according to claim 5, wherein the aliphatic hydrocarbon comprises n- heptane, n-hexane or a mixture thereof.

7. A process according to claim 4, wherein the volume of the aliphatic hydrocarbon comprises more than the volume of dichloromethane.

8. A process according to claim 7, wherein the ratio of the volume of

dichloromethane to the volume of aliphatic hydrocarbon comprises about 2:5.

9. A process according to claim 4, wherein the combined volume of dichloromethane and aliphatic hydrocarbon comprises about 1.5 times to about 4 times more than the weight of amorphous montelukast sodium.

10. A pharmaceutical composition comprising crystalline Form Dl of montelukast sodium and one or more pharmaceutically acceptable excipients.

11. The use of crystalline Form Dl of montelukast sodium for the manufacture of a medicament for the prophylaxis or treatment of asthma in adults or pediatric patients.