DESC:Field of the Invention
The present invention generally relates to the field of process chemistry, and more particularly, relates to process for the preparation of solid active pharmaceutical ingredient, such as montelukast sodium, using anti-solvent crystallization method.

Background of the Invention
Montelukast sodium, chemically (E,Z)-2-(1-((1-(3-(2-(7-Chloroquinolin-2-yl) vinyl) phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propylthio)methyl)cyclopropyl) acetic acid, is a leukotriene receptor antagonist (LTRA) typically used in complementary with corticosteroids or anti-asthmatic agent.

Montelukast sodium, structurally represented as Formula I, is administered orally or by inhalation along with steroids and disclosed in the US Patent No. 5,565,473.

Example 161 of the patent exemplifies preparation of sodium salt of montelukast via free acid, however no details about specific synthesis of both montelukast free acid and Montelukast sodium salt are provided. It refers to the similar reactions in the patent. The similar process describes formation of sodium salt as oil form which was dissolved in water and freeze dried.

US Patent No. 9,487,487 B2 teaches isolation using n-heptane. Ethanolic sodium hydroxide solution was charged to the solution of Montelukast in dichloromethane and stirred for 30 minutes. Dichloromethane was distilled completely at below 40° C to get a residue. Then methanol was charged, stirred at 40°C to 45°C for 30 minutes, treated with activated carbon and filtered. The filtrate was distilled out completely under reduced pressure below 45°C. n-heptane was charged to the residue and distilled out methanol traces completely below 45°C. Again n-heptane was added and stirred for 4 hours at 25°C to 35°C. Precipitated solid was filtered and washed with n-heptane. However, it is difficult to reduce the residual solvent below ICH limits and comply with quality attributes. It requires specialized conditions and technology to achieve the quality of the product.

Other reported isolation techniques are spray drying, freeze drying, however these are not commercially viable. Also, crystallization using the evaporation method is not effective to achieve the quality attributes such as residue on ignition and impurity rejection, solubility and in some cases in physical description.

Thus, there is a need for a cost effective, industrially feasible and practically scalable process which yields montelukast sodium solid that passes all the quality attributes without any further processing.

Summary of the Invention
The present invention provides an improved process for the preparation of solid montelukast sodium using anti-solvent crystallization method.

In an aspect of the present invention, the process comprises steps of (a) preparing a solution of montelukast sodium in a first solvent, (b) adding second solvent to step (b) to obtain a saturated solution, and (c) adding the saturated solution of step (b) in chilled second solvent.

These and other aspects, embodiments and advantages of the present invention will become apparent to those skilled in the art from the following detailed description.

Brief description of the drawings
FIG 1 graphs concentration of montelukast sodium in the solution v/s flow rate of montelukast sodium during addition of montelukast sodium solution to the chilled second solvent.
Detailed Description of the Invention
The following detailed description is the best currently contemplated methods of performing exemplary embodiments of the invention. The description is not to be taken in a listing sense, but is made merely for the purpose of illustrating the general principles of the invention, since the scope of the invention is used defined by the appended claims.

Various inventive features are described below that can each be used independently of one another or in combination with other features. Broadly, embodiments of the present invention generally provide a process for preparing solid montelukast sodium using anti-solvent crystallization method.

Crystallization is the separation of solid crystals from the solution. Primary types of crystallization are evaporation crystallization and cooling crystallization.

The inventors of the present invention have tried the techniques for crystallization of montelukast sodium as disclosed in the prior art. However, in either of these techniques the isolation of stable solid montelukast sodium was difficult. Also, these techniques were not feasible for commercial manufacturing.

Montelukast sodium is a highly polar, light sensitive and hygroscopic compound. The solubility, clear point and cloud point of the compound in the corresponding solvent was studied and tabulated as stated in the Table 1 below.

Sr. No MTK Na (Solute)
gm Solvent Name Solvent volume (ml) Polarity Clear point Cloud point Observation Evaporation
1 1 Methanol 0.5 5.1 25-30 No cloud observed till -20 C On cooling solution becomes very viscous and becomes gummy in nature, but no solid phase forms After evaporation of solvent, the solution concentration increases and becomes thick and as evaporation proceeds the glassy phase forms.
2 1 Ethanol 0.5 25-30
3 1 IPA 1 3.9 25-30
4 1 Water 0.5 10.2 25-30
5 1 Ethyl acetate 0.5 4.4 25-30
6 1 Methyl isobutyl ketone 1 4.2 25-30
7 1 MDC 0.5 3.1 25-30
8 1 Toluene 1 2.4 25-30
9 1 Acetone 0.5 5.1 25-30
Table 1

Referring Table 1, it is understood that the montelukast sodium is highly soluble in polar solvents and the solutions formed were stirrable and clear.

Cloud point is the temperature below which a transparent solution undergoes phase separation. This temperature is very important to decide the crystallization system of any compound. The solutions were cooled gradually from room temperature to -20°C and the results are briefed in Table 1. It was observed that on cooling the viscosity of solution increases drastically and solution gets converted into gummy form. On further stirring, the solution becomes non-stirrable but the expected solid phase separation did not happen and hence falling out of the solid was not observed.

The formation of nuclei and growth of the crystals are the two major steps in the crystallization process. It is the process of energy and mass transfer and the induction time is the elapse of time between creation of supersaturation and detection of nucleation i.e. first crystal formation.

It was observed that the induction period of the montelukast sodium is very high. As the viscosity of the solution increases, diffusivity of dissolved solute molecules decreases drastically and hence in the nucleation instead of distinct solid phase, gummy phase is observed.

Thus, creation of supersaturation by cooling is not effective for montelukast sodium. It was concluded that the cooling crystallization is not feasible.

Hence evaporation crystallization was studied. The clear solution of Montelukast Sodium was heated under controlled vacuum and the solvent evaporated slowly. It was observed that as the evaporation proceeds the solvent quantity decreases and the concentration of solution increases. The system achieves supersaturation, and the solution becomes non-stirrable.

The solid phase was not observed even after prolonged stirring, due to higher induction period and enriched viscosity. Beyond a certain degree of supersaturation, the glassy phase was observed instead of a distinct solid phase.

Thus, supersaturation by evaporation was not effective and hence another method such as anti-solvent crystallization was studied. In anti-solvent crystallization the solution of the compound and solvent in which the solubility of the compound is less or negligible are mixed. The presence of anti-solvent in the solution alters the solubility of the solute in solution. In the certain ratio of solvent and the anti-solvent, the system reaches to the supersaturation and the secondary phase formation occurs.

The solubility of montelukast sodium in certain solvents was studied for screening of anti-solvent for anti-solvent crystallization. The results are described in the TABLE 2.

Sr. No Solvent Name Polarity Solubility
1 Acetonitrile 5.8 Slightly soluble
2 n-heptane 0.1 Practically insoluble
3 cyclohexane 0.2 Practically insoluble
4 Hexane 0.1 Practically insoluble

Table 2
The crystallization of montelukast sodium by anti-solvent method was carried out in two ways.
1. True addition - The anti-solvent is added to the solution of the montelukast sodium.
2. Reverse addition - The montelukast sodium solution is added to the anti-solvent.
In true addition, the experiments along with solvent methanol, ethanol, IPA, ethyl acetate, MDC, acetone and anti-solvent acetonitrile, n-heptane, cyclohexane and hexane were performed. Different process parameters like solvent: anti-solvent ratio, addition temperature, rate of addition, mixing pattern, addition location and seeding considerations were studied.

We observed the oiling out phenomenon in all the above combinations instead of distinct solid formation.

Due to addition of anti-solvent the supersaturation is achieved. When the supersaturation reaches a certain level, the formation of the secondary phase becomes spontaneous, this point is known as metastable zone limit. As the degree of supersaturation is high and induction time is more, the distinct solid formation was not observed. On further antisolvent addition, oiling out was observed.

Oiling-out, also termed “de-mixing” or “liquid–liquid phase separation (LLPS)”, is a phenomenon whereby a second liquid phase instead of a distinct solid phase is formed.

In true addition, further experiments along with solvent Methyl isobutyl ketone and Toluene and anti-solvent Acetonitrile, n-heptane, cyclohexane and hexane were performed. Different process parameters like solvent: anti-solvent ratio, addition temperature, rate of addition, mixing pattern, addition location and seeding considerations were studied.

We observed sticky solid formation in several experiments; however, it is unstable and again solubilizes due to presence of solvent traces.

Thus true addition method is not feasible. Even if not stable, the solid formation was observed in Methyl isobutyl ketone and toluene system. Various experiments were carried out for the stable solid phase formation by changing the process in many ways and to optimize the crystallization kinetics.

To avoid stickiness of the solid, the inventors tried to avoid the trapping of the solvent by dealing with crystallization kinetics. The slower crystallization kinetics results in the more solvent trapping.

The inventors of the present invention performed reverse phase crystallization to increase the crystallization kinetics.

The solution of montelukast sodium in methyl isobutyl ketone or toluene was poured in anti-solvent slowly under stirring at room temperature. The sticky solid formation was observed which gets agglomerated during maintaining. Further to avoid sticky solid formation, the kinetics was improved by lowering the temperature at 0 to 10°C, 0 to -10°C and -10 to -20°C. We found crystal stability increases by decreasing the temperature and solid fall out at -10 to -20 degrees. However the stability of the solid formed was very less and it melted after filtration. Thus it failed in the residual solvent.

From all the above experiments it was concluded that the crystals formed should have energy to sustain the solid-solid and solid-liquid interactions in the system and will not solubilize again in the system and will not melt during filtration and on storage.

This can be explained better with illustrative graph in FIG 1. A graph is plotted for concentration of montelukast sodium in the solution V/S flow rate of Montelukast Sodium during addition of montelukast sodium solution to the chilled second solvent. The graph helps us to understand the kinetics of the system and its behaviour.

Red line in the graph indicates equilibrium solubility line; green line in the graph indicates metastable zone limit; purple line indicates the solution concentration v/s flow of montelukast sodium solution when solution is prepared using neat methyl isobutyl ketone; blue line indicates the solution concentration V/S flow of montelukast sodium solution when solution is prepared as per the process of the present invention.

The stability of the solid formed is less as there is a large difference between equilibrium solubility (indicated by red line in graph) and solution concentration (i.e solid falling out at very higher degree of supersaturation) (indicated by point F2 on purple line in the graph). This difference is to be minimized (adjusted) in such a way that the system will get enough energy to form stable solid. The supersaturation is adjusted (indicated by point F1 on blue line) to form the stable solid with the optimum energy.

The inventors of the present invention achieved this by adding optimum quantity of anti-solvent in montelukast sodium solution.

Due to the addition of anti-solvent, the montelukast sodium solution gets saturated up to certain degrees before adding it in the anti-solvent in the reverse mode. Such a saturated solution with anti-solvent requires less energy to fall out and the solid formation is done in very less time than any other above-described processes. This improved kinetics avoids the trapping of the solvent in the solid as the solid phase formation is faster. This results in the stable solid phase which remains stable during prolonged stirring.

The solid thus formed has a high filtration rate and is stable even during and after filtration.

An embodiment of the present invention relates to a process for the preparation of stable solid montelukast sodium. The process comprises the steps of
(a) preparing a solution of montelukast sodium in a first solvent;
(b) adding second solvent in the solution of step (a) to obtain a saturated solution; and
(c) adding the saturated solution of step (b) slowly in cooled second solvent.
The first solvent is selected from methyl isobutyl ketone, toluene, ethyl acetate.
Preferably the first solvent is selected from methyl isobutyl ketone and toluene. Particularly the first solvent is methyl isobutyl ketone.

The solution in stage (i) is carried out at 35-60°C, preferably at 40-50°C, particularly at 45°C.

The second solvent is selected from n-heptane, DIPE, cyclohexane, n-hexane.
Preferably the second solvent is n-heptane.

The ratio of first solvent to the second solvent in stage (ii) is 1.5-3:0.25-1.5, particularly the ratio is 2:1.

The addition of the second solvent to the solution of stage (ii) is carried out at 25-40°C, preferably at 35°C.

The second solvent in stage (iii) is cooled to 0 to -30°C, preferably the solvent is cooled to -10 to -25°C, particularly the solvent is cooled to -20°C.

The saturated solution of step (b) is slowly added to the previously cooled 8-12V of the second solvent with respect to montelukast sodium used in step (a), preferably in 9-11V, particularly in 10V.

Mode of addition Observation Residual solvent (ppm)
Fast addition Leads to sticky lumps n-Heptane - 30986
Methyl isobutyl ketone - 10002
Slow addition Material crystallized out properly n-heptane - 2640
Methyl isobutyl ketone - 1200

The slow addition crystallizes the material properly, whereas the fast addition leads to the sticky lumps. Due to this the material formed from fast addition fails in residual solvent. Thus, slow addition is mandatory for the formation of particles with the proper energy and with residual solvent within limit.

The feed rate of the mixture of stage (ii) is 5-25% of the feed solution/hour to the anti-solvent. Preferably the feed rate is 10-20% of the feed solution/hour to the anti-solvent.

Particularly the feed rate is 16% of the feed solution/hour to the anti-solvent.

In another preferred embodiment, the present invention provides improved process for synthesis of solid montelukast sodium, wherein the said process comprises the steps of
(ia) preparing a solution of Montelukast sodium in 2V of Methyl isobutyl ketone or toluene at 45-50°C;
(iia) adding n-heptane (1V) to the solution formed in stage (i); and
(iiia) adding the mixture formed in stage (ii) at the feed rate of 16% in n-heptane (10V) cooled to -15 to -20°C.

EXAMPLES
Example 1
Preparation of Montelukast Sodium
Under nitrogen atmosphere Montelukast (100 gm ) was changed to a mixture of methanol (180 ml) and acetonitrile (200 ml) at 30-35°C. The mixture was stirred for 15-20 minutes. 30% sodium methoxide (30 ml) was charged to the reaction mixture and stirred for 45-60 minutes at 30-35°C. The temperature of the reaction mass was raised to 45-50°C.

The slurry of the charcoal was prepared by charging activated charcoal (5 gm) to the methanol (40 ml). To the above reaction mass the charcoal slurry was added. The mass was stirred for 20-30 minutes at 45-50°C. The mass was filtered and washed with Methanol (10 ml). The filtrate was combined and the solvent was distilled out under vacuum at 50-55°C. The Montelukast sodium obtained as oil.

Example 2
Preparation of solid Montelukast sodium
Methyl isobutyl ketone (Methyl isobutyl ketone) (200 ml) was charged to the oil obtained in the Example 1 at room temperature. The mixture was stirred for 30-45 minutes at 30-35°C. The temperature of the reaction mixture was raised to 45-50°C. The mixture was stirred at 45-50°C for 30-45 minutes. The mass was cooled and n-heptane (100 ml) was charged slowly at 30-35°C. The mass was stirred at 30 to 45 minutes. n-heptane (1000 ml) was cooled at -15 to -10°C and the above reaction mass was added to heptane at the rate of 50-60 ml/hour.

The mixture was stirred at -15 to -10°C for 1-2 hours. Montelukast sodium solid was formed and the mass was filtered. The wet cake was washed with n-heptane (100 ml x 2) and cooled to 0 to 5°C.

n-heptane (500 ml) was charged to the wet cake at 30-35°C and the mixture was stirred at 30-35°C for 30-45 minutes under nitrogen. The wet material was unloaded and dried under vacuum for 5-6 hours at temperature NMT 30°C. Montelukast sodium was obtained as a white solid (99 gm, 96% yield), HPLC Purity - 99.57%

Example 3
Preparation of solid Montelukast sodium
Methyl isobutyl ketone (Methyl isobutyl ketone) (340 L) was charged to the Montelukast sodium oil (170 kg) at room temperature. The mixture was stirred for 30-45 minutes at 30-35°C. The temperature of the reaction mixture was raised to 45-50°C. The mixture was stirred at 45-50°C for 30-45 minutes. The mass was cooled and n-heptane (170 L) was charged slowly at 30-35°C. The mass was stirred at 30 to 45 minutes. n-heptane (1700L) was cooled to -10 to -20°C. The above mix was added to the cooled n-heptane under nitrogen. The mixture was stirred at -10 to -20°C for 1-2 hours. Montelukast sodium solid was formed and the mass was filtered. The wet cake was washed with n-heptane (170 L).

n-heptane was charged to the wet cake at 30-35°C and the mixture was stirred at 30-35°C for 30-45 minutes under nitrogen. The wet material was unloaded and dried under vacuum for 5-6 hours at temperature NMT 30°C. Montelukast sodium was obtained as a white solid (164 kg, 96.47% yield), HPLC Purity - 99.80%
,CLAIMS:We claim –
1. A process for the preparation of montelukast sodium comprising steps of –
(a) preparing a solution of montelukast sodium in a first solvent,
(b) adding second solvent to step (a) to obtain a saturated solution, and
(c) adding the saturated solution of step (b) in chilled second solvent.
2. The process as claimed in claim 1, wherein the first solvent is selected from the group consisting of methyl isobutyl ketone, toluene, and ethyl acetate.
3. The process as claimed in claim 2, wherein the first solvent is preferably methyl isobutyl ketone.
4. The process as claimed in claim 1, wherein the second solvent is selected from the group consisting of n-heptane, diisopropyl ether, cyclohexane, and n-hexane.
5. The process as claimed in claim 4, wherein the second solvent is preferably n-heptane.
6. The process as claimed in claim 1, wherein the first solvent and second solvent are in ratio of 2:1.
7. The process as claimed in claim 1, wherein the step (a) is carried out at a temperature of 35 – 60°C.
8. The process as claimed in claim 1, wherein the second solvent is added to step (b) at a temperature of 25 - 40°C.