DESC:FIELD OF THE INVENTION
The present invention relates to an efficient process for the purification of bilastine. More specifically, the present invention relates to a consistently reproducible and industrially advantageous process for the purification of bilastine, wherein level of all impurities has been controlled as per ICH guidelines.
BACKGROUND OF INVENTION
Bilastine is a second-generation antihistamine medication which is used in the treatment of allergic rhino conjunctivitis and urticaria. Bilastine is chemically known as 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazol-2-yl)piperidin-1-yl)ethyl)phenyl]-2- methylpropanoic acid, and represented by Formula I:

Formula I
Bilastine and its synthesis was first time described in the US Patent 5,877,187. As per the process exemplified, bilastine is prepared by reaction of the benzimidazole intermediate with tosylated oxazole intermediate in presence of sodium carbonate in dimethylformamide (DMF) followed by alkylation of obtained intermediate with 1-chloro-2-ethoxyethane to provide oxazole protected bilastine. Cleavage of the said oxazole ring by treating it with 3N hydrochloric acid at reflux temperature gives bilastine. Thereafter, the product is isolated by cooling the reaction mass and adjusting pH to 7 using 50% sodium hydroxide solution. Finally, bilastine is recrystallized in acetone-water. The process is schematically shown below:

The major shortcoming of above-mentioned process is the introduction of oxazoline group and its subsequent hydrolysis inevitably comprised in the process leads to the formation of several by-products, thereby resulting in a poor product yields and quality and making the whole process lengthy and cumbersome. Also, the said patent is silent about the purity of bilastine.
A PCT publication WO2014/188453 unveils a process for the purification of bilastine. As per process exemplified, the mixture of bilastine and n-butanol is heated to 110-115°C and then the reaction mixture is given post-treatment with carbon. Afterwards, the reaction mixture is filtered and cooled at 5-10°C. Finally, the solid is filtered, washed with n-butanol and dried to get pure bilastine.
An Indian patent application IN201641029306 divulges a process for the preparation of highly pure bilastine. In one of the exemplified examples, crude bilastine is dissolved in butyl acetate followed by heating the solution till complete dissolution. The resulting mass is cooled to room temperature and then the separated solid is filtered and washed with butyl acetate. The recrystallization process is repeated again with the same solvent system. Thereafter, the resulting wet material is taken in methanol and then heated to reflux, followed by stirring at reflux temperature. The resulting mixture is filtered through hyflo-bed and then washed the bed with hot methanol. The separated solid is filtered, washed with cold methanol and then dried to obtain pure bilastine. However, the purification process herein involves cumbersome procedures such as multiple crystallizations or isolation steps which results in significant yield loss making the process uneconomical at commercial level.
Another Indian patent application IN202041039492 discloses a purification process of bilastine, wherein process involves addition of bilastine in a mixed solvent of alcohol (methanol and isopropanol) and N,N-dimethylformamide (DMF). Thereafter, the reaction mixture is heated to reflux temperature and then cooled at 25-35°C to get solid. The obtained solid is filtered, washed with alcohol and dried to get pure bilastine.
A Chinese publication CN104151290 discloses a method for preparing a novel crystalline form of bilastine. The process comprises of dissolving bilastine in a mixed solvent (acetone/water) followed by heating till complete dissolution. Thereafter, the reaction mixture is cooled to ambient temperature and the material gets crystallized. Finally, the material is filtered and dried to obtain the novel crystalline form of bilastine.
Another PCT publication WO2023037184 discloses a process for the purification of bilastine. The process comprises of adding bilastine in methanol followed by heating the mixture to reflux temperature of the methanol. In the resulting mixture, acetone is added and then the reaction mass is cooled to 20-25°C, filtered and washed with methanol. To the filtrate, methanol is added and heated to 50-60 °C and stirred for 30 minutes. Thereafter, the reaction mass is filtered and washed with hot methanol followed by cooling the filtrate and stirred for 40 minutes. Finally, the solid is filtered and washed with cold methanol and dried at below 60-70 °C to obtain pure bilastine.

In most of the above-mentioned prior arts, the inventors are either silent about the purity of bilastine or there is significant loss in yield of the final product. This may be attributed due to the presence of impurities which originate mainly during the synthetic process from the raw materials, solvents, intermediate and by-products. In our hands, when we have repeated the purification processes given in the literature, it has been found that the level of impurities at different RRT does not comply with the ICH guidelines. To remove the said impurities, bilastine needs multiple crystallization or isolation steps which enhance the cost of process and even yield of the final product decreases.
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
Even though, in synthetic organic chemistry getting a single end product with 100% purity is seldom wherein there is always a chance of having by-products. Because by-products or impurities can be formed through variety of side reactions, such as incomplete reaction, over reaction, isomerization, dimerization, rearrangement or unwanted reactions between starting materials or intermediate with chemical reagents or catalysts. Such impurities that remain within the formulation or API even in the small amounts can influence quality, safety and efficacy (QSE) of the product, thereby causing serious health hazards. Therefore, the limits and threshold values of those impurities should comply with the limits set and specified by official bodies and legislation (Pharmacopoeias and International conference on Harmonization (ICH) guidelines).
Nevertheless, besides the existing routes of purification of bilastine, to overcome the aforementioned drawbacks associated in the prior art processes for instance multiple purifications/isolation steps and unacceptable level of impurities, there is a continuing need in the art to optimize the purification condition of bilastine which will purge the impurities down to the desired level as per ICH guidelines.

OBJECT OF THE INVENTION
The principal object of the present invention is to provide an improved and industrial advantageous process for the purification of bilastine that overcomes the limitations of the prior methods i.e., multiple purification, tedious isolation procedures, and impurities formation greater than the limits specified as per ICH guidelines.
Another object of the present invention is to provide an effective process for the preparation of bilastine wherein the formation of impurities is controlled at different RRT (relative retention time) levels.
Yet one another object of the present invention is to provide a process for the purification of bilastine using an environmentally benign solvent-antisolvent system.
SUMMARY OF INVENTION
The present invention provides an improved process for the preparation of bilastine in a substantially pure form, wherein the detectable and undetectable impurities are maintained as per ICH guidelines.
In one embodiment, the present invention provides an efficient process for the purification of bilastine of formula I,

Formula I
which comprises of:
i. providing crude bilastine in a mixture of a suitable organic solvent and water,
ii. heating the reaction mass to reflux temperature till dissolution,
iii. cooling the solution obtained in step (ii) at 35-45?,
iv. adding antisolvent to the solution obtained in step (iii),
v. isolating the pure bilastine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an efficient process for the purification of bilastine. More specifically, the process enables better control of the quality of the product by minimizing the formation of impurities at different RRT (Relative retention time) levels.
As used herein, the term ‘crude’ represents a compound having impurities greater than the limits specified as per ICH guidelines, in particular having any known impurity greater than about 0.15% by area percentage of HPLC or any unknown impurity greater than about 0.10% by area percentage of HPLC.
The term “substantially free” herein means bilastine having each known impurity less than about 0.15% by area percentage of HPLC or each unknown impurity less than about 0.10% by area percentage of HPLC. In particular, less than about 0.10% by area percentage of HPLC.
The term “pure” herein refers to purity of bilastine, which is substantially free from one or more impurities and having purity of greater than 99% or more of about 99.5% or more, particularly of about 99.80% or more by area percentage of HPLC and impurity in less than 0.10% w/w by HPLC.
Generally, impurities are identified spectroscopically and/or with another physical method, and then are associated with a peak position, such as that in a chromatogram, or with a spot on a TLC plate. Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is measured in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the “retention time” (RT).
Retention time can vary by a mean value based upon the condition of the instrumentation as well as many other factors. To mitigate the effects such variations, have upon accurate identification of an impurity, those skilled in the art use the “relative retention time” (RRT) to identify impurities. The RRT of an impurity is its retention time divided by the retention time of a reference marker.
The efficient removal of these impurities is important as even at quite low concentrations, they can have an adverse impact on the purity and yield of the final product i.e. bilastine. Impurities in bilastine are undesirable and may be harmful to a patient being treated with a dosage form of the active pharmaceutical ingredient. The basic idea of the invention is to specifically develop an efficient process of purification of bilastine which is substantially free from impurities.
In the first aspect the present invention provides an efficient process for the purification of bilastine. The process comprises of providing crude bilastine in a mixture of a suitable organic solvent and water at 10-20?. The crude bilastine can be prepared by the methods reported in the literature or by the process as given in the present specification which may have impurities greater than the limits specified as per ICH guidelines.
The dissolution of crude bilastine in mixture of the suitable organic solvent and water can be achieved by heating the reaction mixture to reflux temperature of the organic solvent and stirred for 1-2 hours. In particular, the heating of reaction mass can be carried out between 55 °C and 95°C, and preferably between 55°C and 75°C, and more preferably between 60°C and 70°C.
After dissolving bilastine, the solution may be subsequently cooled at 35-45?. Thereafter, in the reaction mixture, an antisolvent can be added and stirred and further cooled at -5- 10?. Surprisingly, the inventors of present application have found that the impurity at a particular RRT purge to a desired level as per ICH guidelines whereas the level of same impurity does not comply with the ICH guidelines when the bilastine is taken in a single solvent followed by addition of antisolvent.
The “suitable organic solvent” used in above reaction can be selected from but are not limited to "hydrocarbon solvent" such as toluene, xylene and the like; "ether solvent" such as methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvent" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvent" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvent" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvent" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvent" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvent" such as methanol, ethanol, n-propanol, iso- propanol, n-butanol, iso-butanol, tert-butanol, ethane- 1,2-diol, propane- 1,2-diol and the like.
In the similar manner the “antisolvent” can be selected from but are not limited to "hydrocarbon solvent" such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvent" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, and the like; "chloro solvent" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvent" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as, n-propanol, iso- propanol, n-butanol, iso-butanol, tert-butanol, ethane- 1,2-diol, propane- 1,2-diol and the like; "polar solvent" such as water; or their mixtures.
After cooling the resulting reaction mass may be subsequently stirred for few minutes to few hours for complete crystallization and then filtration step can be applied at the same temperature. The filtration can be performed, amongst other methods, by passing the solution, dispersion, or slurry through a filter paper, sintered glass filter or other membrane material, by centrifugation, or using Buchner style filter, rosenmund filter or plates, or frame press. Preferably, in-line filtration or safety filtration may be advantageously intercalated in the process disclosed above, to increase the purity of the resulting material.
The reaction mass containing the bilastine obtained in above step may be subjected to usual work up methods such as washing, quenching, an extraction, a pH adjustment, evaporation, a layer separation, decolourization, a carbon treatment, or a combination thereof.
Thereafter, the resulting material can be dried at 50-60? for about 5-25 hours to obtain highly pure bilastine substantially free from impurities as per ICH guidelines. The preferable drying temperature can be 45-55°C and preferably, the solid can be dried for 12-20 hours and more preferably, for 16-18 hours. Drying procedures mentioned above may include all techniques known to those skilled in the art, such as heating, applying vacuum, circulating air or gas, adding a desiccant, evaporating, or the like, or any combination thereof.
According to the invention it is also unexpectedly found that a good reproducibility of process in consistently obtaining bilastine can be obtained by using a preferable solvent-antisolvent technique.
The pure bilastine prepared by using the process of present invention has purity of greater than 99.75%, preferably 99.80% and more preferably greater than 99.83% and all impurities have been reduced to less than 0.10% w/w by HPLC.
In another embodiment of the present invention, crude bilastine can be prepared by hydrolyzing the bilastine methyl ester in the presence of a suitable base in a suitable solvent. Further, the reaction can be carried out at a temperature of about 10°C to the reflux temperature of the solvent.
The suitable base used herein may include an organic base, inorganic base or mixture thereof. The organic bases include, but are not limited to, amines such as diisopropylethylamine (DIPEA), triethylamine (TEA), diethylamine (DEA), pyridine, dimethylaminopyridine 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, N,N-dimethyl aniline, N-methyl morpholine (NMM), N,N-dimethyl amino pyridine (DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo-[2.2.2]octane (DABCO), tetramethylpiperidine, tetramethylguanidine, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof.
Inorganic bases include, but are not limited to alkali or alkaline earth metal carbonate, bicarbonate, hydroxide or phosphate such as potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, sodium phosphate, hydride such as sodium hydride, lithium hydride or potassium hydride, alkoxide such as sodium or potassium methoxide or ethoxide, tertiary butoxide, alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia, alkali metal and alkaline earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like or mixtures thereof.

The “suitable solvent” used in above reaction can be selected from but are not limited to "ether solvent" such as methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and the like; "ketone solvent" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvent" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvent" such as methanol, ethanol, n-propanol, iso- propanol, n-butanol, iso-butanol, tert-butanol, ethane- 1,2-diol, propane- 1,2-diol and the like; "polar solvent" such as water; or their mixtures.

After completion of hydrolysis reaction, the reaction mass can be subjected to usual work up methods for the isolation of crude bilastine.
The process of the present invention provides pure bilastine wherein the level of individual specified, and unspecified impurities is controlled at a level of equal to or less 0.1% respectively and total impurities at a level of equal to or less than 0.2% as per ICH guidelines.

Although the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.

EXAMPLES
Example 1: Purification of bilastine
Bilastine (20 g) (having HPLC purity[w/w] =99.59%; one impurity=0.23% at RRT 0.98) was taken in methanol (20 ml) and the reaction mixture was stirred at 10-20°C followed by addition of water (5ml). Thereafter, the reaction mixture was heated at 60-70°C and stirred for 0.5-1 hour. The resulting solution was allowed to cool at 35-45°C. Further, in the reaction mixture, acetone (80ml) was added and stirred. Afterwards, the reaction mass was cooled at -5 to 5°C and again stirred for 1 hour. Then, the reaction mass was isolated as wet cake by filtration at -5 to 5°C followed by washing with acetone (5 ml). Finally, the wet cake was dried at 55-65°C for 10-20 hours to get pure bilastine (18.6g) having HPLC purity[w/w]: 99.88%; one impurity=0.06% at RRT 0.98.
Example 2: Purification of bilastine
Bilastine (20 g) (having HPLC purity[w/w] =99.59%; one impurity=0.23% at RRT 0.98) was taken in methanol (20 ml) and the reaction mixture was stirred at 10-20°C followed by addition of water (5ml). Thereafter, the reaction mixture was heated at 60-70°C and stirred for 0.5-1 hour. The resulting solution was allowed to cool at 35-45°C. Further, in the reaction mixture, acetone (80ml) was added and stirred. Afterwards, the reaction mass was cooled at -5 to 5°C and again stirred for 1 hour. Then, the reaction mass was isolated as wet cake by filtration at -5 to 5°C followed by washing with acetone (5 ml). Finally, the wet cake was dried at 55-65°C for 10-20 hours to get pure bilastine (18.6g) having HPLC purity[w/w]: 99.89%; one impurity=0.06% at RRT 0.98.
Example 3: Purification of bilastine
Bilastine (20 g) (having HPLC purity[w/w] =99.59%; one impurity=0.23% at RRT 0.98) was taken in methanol (20 ml) and the reaction mixture was stirred at 10-20°C followed by addition of water (5ml). Thereafter, the reaction mixture was heated at 60-70°C and stirred for 0.5-1 hour. The resulting solution was allowed to cool at 35-45°C. Further, in the reaction mixture, acetone (80ml) was added and stirred. Afterwards, the reaction mass was cooled at -5 to 5°C and again stirred for 1 hour. Then, the reaction mass was isolated as wet cake by filtration at -5 to 5°C followed by washing with acetone (5 ml). Finally, the wet cake was dried at 55-65°C for 10-20 hours to get pure bilastine (18.6g) having HPLC purity[w/w]: 99.83%; one impurity=0.10% at RRT 0.98.
Comparative Examples
Example 1: Purification of bilastine
Bilastine (10 g) (having HPLC purity[w/w] =99.10%; one impurity=0.18% at RRT 0.98) was taken in methanol (30 ml) and the reaction mixture was stirred at 10-20°C. Thereafter, the reaction mixture was heated at 60-70°C and stirred for 0.5-1 hour. The resulting solution was allowed to cool at 35-45°C. Afterwards, the reaction mass was cooled at -5 to 5°C and again stirred for 1 hour. Then, the reaction mass was isolated as wet cake by filtration at -5 to 5°C followed by washing with methanol (2.5 ml). Finally, the wet cake was dried at 55-65°C for 10-20 hours to get bilastine (6 g) having HPLC purity[w/w]: 99.78%; one impurity=0.14% at RRT 0.98.
Example 2: Purification of bilastine
Bilastine (20 g) (having HPLC purity[w/w] =99.59%; one impurity=0.23% at RRT 0.98) was taken in methanol (30 ml) and the reaction mixture was stirred at 10-20°C. Thereafter, the reaction mixture was heated at 60-70°C and stirred for 0.5-1 hour. The resulting solution was allowed to cool at 35-45°C. Further, in the reaction mixture, acetone (80ml) was added and stirred. Afterwards, the reaction mass was cooled at -5 to 5°C and again stirred for 1 hour. Then, the reaction mass was isolated as wet cake by filtration at -5 to 5°C followed by washing with acetone (5 ml). Finally, the wet cake was dried at 55-65°C for 18 hours to get bilastine (18.6 g) having HPLC purity[w/w]: 99.36%; one impurity=0.52% at RRT 0.98.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
,CLAIMS:We claim:
1. A process for the purification of bilastine of formula I,

Formula I
which comprises of:
i. providing crude bilastine in a mixture of a suitable organic solvent and water,
ii. heating the reaction mass to reflux temperature till dissolution,
iii. cooling the solution obtained in step (ii) at 35-45?,
iv. adding an antisolvent to the solution obtained in step (iii),
v. isolating the pure bilastine.

2. The process as claimed in claim 1, wherein organic solvent in step (i) is selected from hydrocarbon solvent; ether solvent; ester solvent; polar-aprotic solvent; chloro solvent; nitrile solvent and alcohol solvent.

3. The process as claimed in claim 2, wherein hydrocarbon solvent is selected from toluene, xylene and the like; ether solvent is selected from methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and the like; ester solvent is selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, tert-butyl acetate and the like; polar-aprotic solvent is selected from dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; chloro solvent is selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; nitrile solvent is selected from acetonitrile, propionitrile, isobutyronitrile and the like; alcohol solvent is selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol and the like.

4. The process as claimed in claim 1, wherein heating of reaction mass in step (ii) is carried out between 55°C and 95°C.

5. The process as claimed in claim 4, wherein heating of reaction mass is carried out between 60°C and 70°C.

6. The process as claimed in claim 1, wherein antisolvent in step (iv) is selected from hydrocarbon solvent; ether solvent; chloro solvent; ketone solvent; and nitrile solvent.

7. The process as claimed in claim 6, wherein hydrocarbon solvent is selected from n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; ether solvent is selected from dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, and the like; chloro solvent is selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; ketone solvents is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitrile solvent is selected from acetonitrile, propionitrile, isobutyronitrile and the like; or their mixtures.

8. The process as claimed in claim 1, wherein after addition of antisolvent, reaction mass is further cooled to -5- 10? to isolate pure bilastine.

9. The process as claimed in claim 1, wherein bilastine has purity of greater than 99.75% w/w by HPLC.

10. The process as claimed in claim 1, wherein level of unknown impurity at RRT 0.98 is reduced from 0.23% w/w to less than 0.10%, as determined by HPLC, in pure bilastine.