This invention relates to A Novel Crystalline Form Of Montelukast Sodium And Process Therefor.
FIELD OF INVENTION
This invention relates to a novel crystalline form of montelukast sodium, the leukotriene inhibitor, designated as 'Form C and herein after referred to as 'form C\ The new crystalline form C may be anhydrous, hydrated or solvated. The form C is highly pure, less moisture sensitive and has less residual solvent.
The present invention also provides a method for the preparation of a form C. Further, the method disclosed herein after is industrially feasible, high yielding and commercially profitable. More particularly, the method of present invention relates to conversion of amorphous montelukast sodium to crystalline form C by simply stirring it in acetonitrile.
BACKGROUND OF THE INVENTION:
(Formula Removed)
Montelukast Sodium (I)
Montelukast sodium is chemically described as [R-(E)]-l-[[[l-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[(l-hydroxy-1-methylethyl) phenyl]propyl]thio]methyl] cyclopropaneacetic acid, sodium salt and is known to be a therapeutically useful compound. Its empirical formula and molecular weight are C35H35CINNa03S and 608.17 respectively. Montelukast sodium displays the structural formula (I). It is a optically active, highly hygroscopic, white to off-white powder, freely soluble in ethanol, methanol and water and practically insoluble in acetonitrile.
US Patent No.5,614,632 advocates the preparation of montelukast sodium in crystalline form A wherein montelukast acid, generated in-situ in toluene, by treating DCHA salt, with dilute acetic acid, is directly converted into montelukast sodium (I) by reacting with sodium hydroxide. Repeated recovery of solvents along with seeding of the difficult to obtain crystals and by slowly adding excess of acetonitrile to the toluene
solution at +40±2 C affords montelukast sodium in crystalline form A. After the addition of acetonitrile, the slurry of crystalline montelukast sodium (I) is aged for 12 to 16 hrs at +40+2 C. In order to obtain montelukast sodium (I) in pure and crystalline form, the DCHA salt with purity >99% is used and seeding plays a very crucial role during crystallization. Our experience in the laboratory has indicated that it is very difficult to reproduce the preparation of crystalline form via the methods mentioned in the above patent (US 5,614,632). The crystalline form A of montelukast sodium displays XRD pattern, which notably exhibits 29 peaks at 4.60, 6.2, 6.5, 6.9, 9.8, 10.2, 13.1, 15.7, 16.4, 17.7, 18.6, 19.7, 21.6, and 23.9,
PCT WO 2004/091618 Al ('618) describes and claims new polymorphic form of montelukast sodium designated as 'Form B' along with its hemi and monosolvate and a process therefor.
The Form B as claimed in '618 is characterized by x-ray powder diffraction unique peaks at 2 9 = 5.4, 5.7, 9.5, 10.4, 17.1, 18.7, & 21.6. According to the process claimed and disclosed in '618, Form A that is substantially free from amorphous montelukast sodium is prepared by contacting amorphous montelukast sodium or mixture of amorphous and Form A with acetonitrile to form montelukast sodiumracetonitrile monosolvate; collecting monosolvate and removing acetonitrile. The process, as described, teaches stirring amorphous or mixture of
amorphous and crystalline form A in acetonitrile at 70 C for 24 hours.
The invention further teaches preparation of Form B wherein the process comprises adding amorphous montelukast sodium or mixture of
amorphous and Form A to liquid acetonitrile with no or limited stirring or
agitation at a temperature up to 80 C preferably at 55 C to 70 C to
produce Form A that is substantially free from amorphous form, then
stirring the Form A thus obtained with acetonitrile at about 50 C for
about 4 hours to produce sodium:acetonitrile monosolvate followed by stirring sodium:acetonitrile monosolvate in acetonitrile at temperature up
to 50 C for about 4 hours to produce hemisolvate then removing
acetonitrile to yield Form B.
Example 1 describes preparation of Form B by stirring suspension of
Form A in acetonitrile at 70 C for 4 hours followed by cooling and
filtering under house of nitrogen.
It may be pertinent to note that the application '618 that is incorporated
by way of reference substantiates only using Form A as a starting
material for the production of Form B. Further, it appears that the form A
has to be substantially free from amorphous form. This leads one to infer
that the amorphous form may be posing problems in obtaining crystalline
form.
As is clear from the description herein above, the process for generating crystalline form A, the starting material, of Form B suffers from several drawbacks and involves steps that are lengthy, tedious, non-reproducible and require stringent conditions. Additionally, they require intermediates of high purity, which may have to be chromatographically purified.
Therefore, there is a need for developing novel crystalline forms of montelukast sodium and a process for preparation thereof, which is simple and reproducible, scaleable and substantially obviates if not overcome fully the above-mentioned drawbacks.
SUMMARY OF THE INVENTION:
It is, therefore, an object of the present invention to provide a novel crystalline form montelukast sodium, the leukotriene inhibitor, designated as 'Form C and herein after referred to as 'form C
Other object of the invention is to provide new crystalline form C that may be anhydrous, hydrated or solvated.
Another object of the invention is to provide new crystalline form C, which is highly pure in terms of residual solvent, and less moisture sensitive.
The present invention also provides a method for the preparation of a form C, which eliminates the major problems associated with the existing processes.
Further, the method disclosed herein after is industrially feasible, high yielding, time and cost effective, and commercially profitable.
More specifically the method of present invention relates to conversion of amorphous montelukast sodium to crystalline form C by simply stirring amorphous montelukast sodium in acetonitrile there by avoiding using crystalline Form A as a starting material.
Thus the present invention avoids tedious & time consuming process for preparing crystalline Form A.
STATEMENT OF THE INVENTION
Accordingly, the present invention provides a new crystalline form of montelukast sodium salt (Form C), including anhydrous, hydrated and solvated forms characterized by XRD strong unique peaks at 20 = 7.76, 20.02,20.64,21.14.
According to one of the embodiments of this invention, the strongest peak of from C at 20= 21.14 (99%) is not present in any one of the reported forms.
The peaks for Form A, Form B are also shown in Table 1 and Table 2 along with those of Mono and hemi solvate of form B respectively, which have been described in the patent applications mentioned herein above.
The evaluation of the comparative data clearly shows that the new crystalline form C of Montelukast sodium is distinctly different from Form A and Form B and the mono and hemihydrates of Form B.
TABLE I

(Table Removed)
Table II

(Table Removed)
According to another aspect of the present invention, there is provided a method for the preparation of the crystalline Form C comprising stirring amorphous montelukast sodium in acetonitrile till completion of crystallization followed by recovering the Form C by conventional methods.
According to one of the embodiments of this invention the volume of acetonitrile may be 2-100 times of montelukast amorphous, preferably 5-50 times, more preferably 7-20 times and most preferably 10-15 times.
According to another embodiment the reaction with acetonitrile may be effected at a temperature ranging from 0-50°C, preferably 5-50°C, more preferably 10-40°C and most preferably 25-40°C.
Further the reaction may be carried out for a period of 10-50 hours, preferably 15-50 hours, more preferably 24-48 hours and most preferably 36-48 hours
The montelukast amorphous may be prepared bythe following steps:
(a) converting the pure DCHA salt into montelukast acid in pure form by reacting it with dilute acid in a water immiscible solvent like toluene and isolating the montelukast acid in crystalline form and then
(b) reacting the pure Montelukast acid so obtained in a polar protic solvent with a source of sodium ion followed by evaporating the solvent to obtain the amorphous montelukast sodium.
Alternately the amorphous form may be prepared by
(a) converting the pure DCHA salt into montelukast acid by reacting with dilute acid in a water immiscible solvent like toluene, washing with water, recovering the solvent under vacuum to obtain the residue of montelukast acid in viscous or powder form and then,
(b) reacting above residue or powder of montelukast acid with a source of sodium ion in a polar protic solvent like methanol or ethanol to obtain solution of sodium salt of montelukast, further adding polar
aprotic solvent like acetonitrile, followed by recovery of solvents under vacuum optionally adding aprotic solvent to compensate for the loss of solvent, and repeating till less than 1% of the alcoholic solvent is left in the mixture (monitored by gas chromatographic analysis).
In the most appropriate embodiment of above transformation, a suspension of crude DCHA salt in toluene and water is treated with 2N acetic acid at +25 to +35°C for 15-20 min., the organic layer is separated, washed with water and stirred at +25 to +35°C for 6-8 hrs. The resulting light pale yellow crystals of pure montelukast acid are filtered and dried under vacuum.
Finally, the purified Montelukast acid is dissolved at ambient temperature preferably in lower aliphatic alcohols like methanol or ethanol and reacted with 1.05 to 1.10 molar equivalents of sodium hydroxide to form a solution of sodium salt of Montelukast. The solvent is evaporated under high vacuum at +05 to +50°C, most appropriately at +35 to +40°C. The viscous oily or foamy solid that is formed after the evaporation of alcoholic solvent is triturated with non polar solvents like cyclopentane, n-pentane, cyclohexane, n-hexane, cycloheptane, or n-heptane, at 0 to +50°C, most appropriately at +25 to +35°C and stirred for 0.5 to 6 hrs, preferably for 1 to 2 hrs. The solid is filtered off and dried <+40°C under vacuum to obtain pure montelukast sodium (I) as a white amorphous powder. The resulting amorphous montelukast sodium is then stirred with acetonitrile for 12-48 hrs during which time the amorphous powder gets converted into the new polymorphic form C and the resulting crystalline solid is filtered off and dried under vacuum.
Alternatively Montelukast sodium (I) as an amorphous powder may be prepared from any conventional method and can be converted to Form C by stirring with acetonitrile for 12-48 hrs during which time the amorphous powder gets converted into the new polymorphic form C and the resulting crystalline solid is filtered off and dried under vacuum.
DESCRIPTION OF THE DRAWING:
Fig 1: depicts the X-Ray diffraction pattern of Polymorphic form C
The invention may further be explained by taking following examples though these should not restrict the scope of invention.
EXAMPLE I: PREPARATION OF FORM C:
Montelukast sodium amorphous, 10 g was suspended in 50 ml of acetonitrile and was stirred for 40 hrs at 35-40°C, resultant solid was filtered and dried under vacuum to get 8.5 g of Form C.
ADVANTAGES:
(1) The form C is more pure in terms of residual solvent
(2) The form C is less moisture sensitive.
(3) The process for preparing form C is simple as well as time and cost effective, industrially feasible and commercially profitable, convenient to operation on commercial scale.

WE CLAIM:

1. A new crystalline form of montelukast sodium salt (Form C), including anhydrous, hydrated and solvated forms characterized by XRD strong unique peaks having 2 theta values as 21.14, 16.92, 18.44, 16.40 (±0.5)
2. A new crystalline form as claimed in claim lis further characterized by following XRD pattern 7.76, 9.28, 11.76, 15.70, 16.40, 16.92, 17.98, 18.44, 20.02, 20.64, 21.14, 21.70, 23.80
3. A Process for the preparation of the crystalline form of montelukast sodium (Form C) comprising stirring amorphous montelukast sodium in acetonitrile till completion of crystallization followed by recovering the Form C by conventional methods.
4. A Process as claimed in claim 3 wherein the volume of acetonitrile used is 2-100 times of montelukast amorphous, preferably 5-50 times, more preferably 7-20 times and most preferably 10-15 times.
5. A Process as claimed in claim 3 wherein the reaction is carried out at a temperature is 0-50°C, preferably 5-50°C, more preferably 10-40°C and most preferably 25-40°C

6. A Process as claimed in claim 3 wherein the reaction is conducted for a period of 10-50 hours, preferably 15-50 hours, more preferably 24-48 hours and most preferably 36-48 hours.
7. A Novel Crystalline Form Of Montelukast Sodium And Process Therefor substantially as herein described.