WO2019175722A1

WO2019175722A1 - Process for the preparation of stable and highly pure crystalline form 2 of bilastine

Info

Publication number: WO2019175722A1
Application number: PCT/IB2019/051876
Authority: WO
Inventors: Dodda Mohan Rao; Bingi Venugopal
Original assignee: Symed Labs Limited
Priority date: 2018-03-12
Filing date: 2019-03-08
Publication date: 2019-09-19

Abstract

Disclosed herein is a consistently reproducible process for the production of highly pure and stable crystalline Form 2 of Bilastine essentially free of other polymorphic forms. Provided also herein is a pharmaceutical composition comprising the highly pure crystalline Form 2 of Bilastine essentially free from other crystalline forms made by the process disclosed herein, and one or more pharmaceutically acceptable excipients.

Description

PROCESS FOR THE PREPARATION OF STABLE AND HIGHLY PURE CRYSTALLINE FORM 2 OF BILASTINE

CROSS REFERENCE TO RELATED APPLICATION

This patent application claims the benefit of priority to Indian Patent

Application No. 201841008936, filed on March 12, 2018, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a consistently reproducible process for the production of highly pure and stable crystalline Form 2 of Bilastine essentially free of other polymorphic forms.

BACKGROUND OF THE INVENTION

U.S. Patent No. 5,877,187 (hereinafter referred to as the US‘l87 patent) discloses a variety of benzimidazole derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds have high Hi antihistaminic and antiallergic activity and are devoid of effects on the central nervous and cardiovascular systems. Among them, Bilastine, chemically named 2-[4-[2-[4-[l-(2-ethoxyethyl)-benzimidazol-2-yl]piperidin-l- yl]ethyl]phenyl]-2-methylpropanoic acid, is a selective histamine Hi receptor antagonist used for treatment of allergic rhinoconjunctivitis and urticaria (hives). Bilastine is represented by the following structural formula I:

Bilastine, a novel second-generation Hi-antihistamine, is approved for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria in adults and children over 12 years of age. Bilastine has a favourable pharmacokinetic profile, being rapidly absorbed resulting in an onset of clinical effect within one hour of administration, and has a long duration of action, exceeding 24 hours, which allows for once-daily dosing.

Bilastine was developed by FAES Farma and approved in the European Union for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. Bilastine is marketed under the trade names Bilaxten^® (in Spain, Colombia, Australia, and several other countries), Ilaxten^® (in United Kingdom), and Blexten™(in Canada).

The synthesis of Bilastine was first described in the U.S. Patent No. 5,877,187. As per the process exemplified in Example 2 of the US’l87 patent, Bilastine is prepared by reacting l-(2-ethoxyethyl)-2-l-(2-(4-(l -(4, 4-dimethyl- A2-oxazoline-2- yl)-l-methylethyl) phenyl)ethyl)piperidine-4-yl-lH-benzimidazole with 3N Hydrochloric acid at reflux temperature to produce a reaction mass containing 2-4-(2- (4-(l-(2-ethoxyethyl)benzimidazole-2-yl)piperidine-l-yl)ethyl)phenyl-2-methyl propanoic acid (Bilastine), followed by cooling the reaction mass and adjusting pH to 7 with 50% sodium hydroxide. The solution was extracted with n-butanol, washed with water, dried over anhydrous sodium sulphate and concentrated. Methanol and 50% sodium hydroxide were added to the residue and refluxed for thirty minutes. The methanol was distilled off and water was added until dissolution was complete. This was extracted with ether and the aqueous layer was taken to pH 7 with 20% HC1 and saturated with sodium chloride, whereupon a solid precipitated which was filtered, washed repeatedly with water and dried in a vacuum dryer at 50°C to yield Bilastine.

Bilastine is known to exhibit polymorphism and various crystalline forms and process for their preparation are apparently disclosed in U.S. Patent No. 7,612,095; PCT Publication Nos. WO 2014/026657; WO 2017/167949; WO 2017/017301; WO 2017/191651 and Chinese Patent Application Publication Nos. CN 103214454 A; CN 103613579 A; CN 103755683 A; CN 104151290 A; CN 104447682 A; CN 104447683 A and CN 103788062 A.

U.S. Patent No. 7,612,095 (hereinafter referred to as the US’095 patent), assigned to Faes Farma, discloses three crystalline forms of Bilastine namely Form 1, Form 2 and Form 3, process for preparation of Form 1, and characterizes the crystalline form 1 by X-ray crystallographic analysis with lattice parameters, Infrared absorption spectrum (IR) and melting point. The US’095 patent characterizes the crystalline form 2 and form 3 by Infrared absorption spectrum (IR) and melting point. The US’095 patent teaches that when Bilastine was originally produced, for example, as per the process described in the product patent US 5,877,187, it was a mixture of form 2 and form 3. Further, US’095 patent discloses that, crystalline form

1 and form 2 are stable and crystalline form 3 is not very stable, both crystalline form

2 and form 3 are converted into crystalline form 1.

According to the US’095 patent, the crystalline form 1 of Bilastine is characterized by X-ray crystallographic analysis, with approximate crystal parameters as follows: Crystallographic system: Monoclinic; Spatial group : P2(l)/c; Crystal size : 0.56 x 0.45 x 0.24 mm; Cell dimensions : a = 23.38 (5) A⁰, a = 90°; b = 8.829 (17) A°, b = 90°; c = 12.59 (2) A°, g = 90°; Volume : 2600 A³; Z, calculated density : 4, 1.184 mg/m . The crystalline form 1 of Bilastine is further characterized by an infrared absorption spectrum in potassium bromide having the characteristic absorption bands at 3430 (s), 3057 (w), 2970 (s), 2929 (s), 2883 (m), 2857 (m), 2797 (w), 1667 (m), 1614 (m), 1567 (w), 1509 (s), 1481 (m), 1459 (vs), (1431 (m), 1378 (w), 1346 (m), 1326 (m), 1288 (w), 1254 (m), 1199 (w), 1157 (w), 1121 (vs), 1045 (w), 1020 (w), 1010 (w), 991 (w), 973 (w), 945 (w), 829 (w), 742 (s), 723 (w), 630 (w) cm ¹; where (w) = weak intensity, (m) = medium intensity, (s) = strong intensity, (vs) = very strong intensity. The crystalline form 1 of Bilastine is further characterized by having a melting point of 200.3°C.

According to the US’095 patent, the crystalline form 2 of Bilastine is characterized by an infrared absorption spectrum in potassium bromide having the characteristic absorption bands at 3429 (s), 3053 (w), 2970 (s), 2932 (s), 2868 (s), 2804 (w), 1699 (m), 1614 (m), 1567 (m), 1508 (s), 1461 (vs)*, 1381 (m), 1351 (s),

1331 (m), 1255 (m), 1201 (w), 1156 (m), 1121 (vs), 1048 (w), 995 (w), 823 (w), 767

(w), 744 (s), 724 (d), 630 (w) cm ¹. The crystalline form 2 of Bilastine is further characterized by having a melting point of 205.2°C.

According to the US’095 patent, the crystalline form 3 of Bilastine is characterized by an infrared (IR) absorption spectrum in potassium bromide having the characteristic absorption bands at 3430 (s), 3053 (w), 2970 (s), 2932 (s), 2868 (s), 2804 (w), 1921 (w), 1708 (m), 1614 (m), 1568 (m), 1508 (s), 1461 (vs), 1380 (m),

1351 (m), 1330 (m), 1271 (m), 1255 (m), 1201 (w), 1156 (m), 1121 (vs), 1048 (w), 995 (w), 823 (m), 767 (w), 744 (s), 724 (w), 630 (w) cm ¹. The crystalline form 3 is further characterized by having a melting point of 197.0°C.

However, the US’095 patent neither discloses nor teaches any process for the preparation of pure crystalline form 2 of Bilastine essentially free of other polymorphic forms.

PCT Publication No. WO 2014/026657 (Applicant: Zentiva, hereinafter referred to as the WO’657 publication) describes a process for the preparation of Bilastine polymorph form 1 by purifying crude Bilastine by crystallization from isopropanol, which is characterized by having a powder X-ray diffraction (XRPD) pattern having peaks expressed as 2-theta angle positions and their corresponding relative intensities (rel. int%) at about 3.64 (4.4), 10.57 (23.3), 11.27 (78.1), 12.47

(38.8), 14.08 (26.9), 15.07 (38.4), 15.50 (16.5), 16.27 (43.6), 17.16 (100.0), 18.89

(71.8), 19.73 (74.0), 21.13 (33.9), 22.17 (18.1), 22.71 (26.9), 23.34 (10.3), 24.88 (18.6), 25.82 (9.2), 26.58 (11.5), 28.43 (9.7), 29.16 (8.8), 30.92 (4.6), 34.38 (9.5), 37.01 (5.4).

The WO’657 publication also describes a process for the Bilastine polymorph form 2 by crystallization of the API from n-pentanol, which is characterized by having a powder X-ray diffraction (XRPD) pattern having peaks expressed as 2-theta angle positions and their corresponding relative intensities (rel. int%) at about 6.53 (100.0), 9.43 (30.8), 11.04 (22.8), 13.39 (6.2), 15.24 (32.2), 15.86 (86.1), 18.07 (29.9), 18.39 (36.2), 18.94 (8.3), 20.19 (16.0), 20.66 (19.0), 21.70 (17.1), 22.17 (15.6), 23.70 (5.7), 26.59 (4.9), 28.03 (3.6), 28.33 (3.6), 29.70 (4.3).

However, the process described in the WO’657 publication has failed to produce pure crystalline form 2 of Bilastine essentially free of other polymorphic forms since the reported XRPD data of the crystalline form 2 of Bilastine is found to contain some additional XRPD 2-theta angle peaks (which are not pertaining to the actual form 2) at about 15.24, 20.66, 21.7, 23.7 and 28.03 ± 0.2 degrees. Moreover, some of the characteristic peaks of form 2 are absent in the XRPD data of the crystalline form 2 reported in the WO’657 publication. Hence, the crystalline form 2 obtained by the process described in the WO’657 publication is not the actual crystalline form 2 that was originally reported in the US’095 patent. PCT Publication No. WO 2017/167949 (Applicant: KRKA, hereinafter referred to as WO’949 publication) discloses two crystalline forms Kl, K2 of Bilastine, processes for their preparation, pharmaceutical compositions and characterizes by X-ray powder diffraction (XRPD), FT-IR spectrum and Differential Scanning Calorimetric (DSC) thermogram.

According to the WO’949 publication, crystalline form Kl of Bilastine is characterized by an XRPD pattern having 2-theta peaks at 9.5, 12.1, 14.9, 18.1, 19.1, 20.1, 21.4, 23.2 and 27.8 ± 0.2 degrees and crystalline form K2 is characterized by an XRPD pattern having 2-theta peaks at 7.7, 10.4, 12.9, 14.5, 16.2, 18.1, 20.3, 22.2 and 29.1 ± 0.2 degrees. Further, the crystalline form Kl is characterized by a DSC thermogram having an Onset at 203.73°C and a Peak at 205.33°C, and the crystalline form K2 is characterized by a DSC thermogram having an Onset at 203.85°C and a Peak at 205.33°C.

PCT Publication No. WO 2017/017301 (Applicant: URQUIMA, S.A, hereinafter referred to as the WO’30l publication) discloses Bilastine crystalline forms Alpha, Beta, Delta, Epsilon, Gamma form A, Gamma form B, Zeta and Eta, processes for their preparation and characterizes them by X-ray powder diffraction (XRPD) diagram, Differential Scanning Calorimetric (DSC) and Thermogravimetric Analysis (TGA). It further discloses the processes for the preparation of Bilastine crystalline form 1, form 2, form 3 and characterizes them by X-ray powder diffraction (XRPD) diagram, Differential Scanning Calorimetric (DSC) thermogram and Thermogravimetric Analysis (TGA).

According to the WO’30l publication, the crystalline form 1 of Bilastine is prepared by dissolving 20 mg of Bilastine in 0.5 ml of methanol at 60°C and the solution was slowly cooled to room temperature. After 24 hours, the solid crystallized and was subsequently filtered and dried in vacuum to produce crystalline form 1 of Bilastine.

According to the WO’30l publication, Bilastine crystalline form Alpha is characterized by an XRPD pattern having 2-theta peaks at 8.7, 10.9, 11.6, 12.2, 13.4, 13.8, 14.0, 14.5, 15.0, 16.1, 17.4, 17.7, 18.6, 18.8, 20.1, 20.7, 21.1, 21.4, 21.7, 21.9, 22.6, 23.3 and 23.5 ± 0.2 degrees; Bilastine crystalline form Beta is characterized by an XRPD pattern having 2-theta peaks at 3.1, 6.0, 9.3, 9.5, 10.0, 10.3, 10.9, 11.4, 12.3, 15.0, 18.2 and 21.8 ± 0.2 degrees; Bilastine crystalline form Delta is characterized by an XRPD pattern having 2-theta peaks at 5.3, 8.8, 9.0, 10.6, 10.9, 13.4, 15.9, 17.2, 17.7, 18.0, 18.9, 19.4, 20.0, 20.2, 20.8, 21.0, 21.2 and 24.7 ± 0.2 degrees; Bilastine crystalline form Epsilon is characterized by an XRPD pattern having 2-theta peaks at

5.6, 9.2, 16.4, 16.7, 16.9, 17.9, 18.4, 20.2 and 22.9 ± 0.2 degrees; Bilastine crystalline form Gamma Form A is characterized by having an XRPD pattern having 2-theta peaks at 7.0, 10.0, 11.1, 12.6, 14.0, 14.6, 16.0, 17.0, 17.8, 18.0, 19.1, 21.1, 22.4, 22.5, 23.9 and 24.2 ± 0.2 degrees; Bilastine crystalline form Gamma Form B is characterized by an XRPD pattern having 2-theta peaks at 9.0, 9.9, 10.1, 12.4, 15.8,

16.3, 17.6, 18.1, 18.5, 19.0, 19.8, 20.9, 21.2, 21.9 and 22.7 ± 0.2 degrees; Bilastine crystalline form Eta is characterized by an XRPD pattern having 2-theta peaks at 8.4,

9.6, 12.2, 13.2, 14.0, 15.1, 16.8, 17.5, 18.2, 19.2, 19.7, 20.3, 21.5, 23.4, and 25.5 ± 0.2 degrees; Bilastine crystalline form Zeta is characterized by an XRPD pattern having 2- theta peaks at 7.8, 8.9, 10.5, 10.6, 11.7, 13.0, 13.6, 14.7, 15.6, 16.3, 18.3, 20.4, 20.7,

21.4, 22.0, 22.4, 22.9, 23.1, 23.3 and 24.2 ± 0.2 degrees.

PCT Publication No. WO 2017/191651 (Applicant: MSN Faboratories Private Fimited, hereinafter referred to as the WO’65l publication) discloses Bilastine crystalline form-M, pure amorphous form, amorphous solid dispersions, processes for their preparation. This PCT publication also describes processes for the preparation of Bilastine crystalline form-l, form-2 and form-3.

According to the WO’65l publication, Bilastine crystalline form 2 is prepared by adding Bilastine (50 gm) to a mixture of methanol (100 ml) and dichloro methane (400 ml) at 25-30°C; the reaction mixture is stirred for 20 min at the same temperature; the obtained solution is slowly added to a pre-cooled mixture of methyl tert. butyl ether (2000 ml) and cyclohexane (500 ml) containing crystalline form-2 seeding material (5 gm) at -5°C to -l0°C, the reaction mixture is stirred for 45 minutes at the same temperature, the separated solid is filtered and then dried the material to get 50 gm of crystalline form 2 of Bilastine having a melting point of 205.3°C.

CN 103214454 A (hereinafter referred to as the CN’454 publication) discloses a crystalline form of Bilastine characterized by an XRPD pattern having 2-theta peaks at 9.27, 10.90, 12.74, 15.66, 17.68, 18.32, 20.03, 21.90 and 27.35 ± 0.2 degrees; and a melting point of l97-200°C. According to the CN’454 publication, crystalline form of Bilastine is prepared by adding methanol (8 ml) to Bilastine (1 g), the mixture is heated to refluxed for one hour, naturally cooled to crystallize, the separated solid is filtered and dried under vacuum at 50°C for 10 hours. The XRPD data and the melting point data reported in the CN’454 publication reveals that the crystalline form of Bilastine obtained is a mixture of crystalline forms.

CN103788062A (hereinafter referred to as CN’062 publication) discloses a crystalline form of Bilastine and characterized by an XRPD pattern having 2-theta peaks at 11.30, 12.50, 17.18, 18.94, 19.80, 21.14, 22.68 and 24.92 ± 0.2 degrees. The crystalline form is produced by dissolving Bilastine in isopropyl alcohol under nitrogen atmosphere, heating the mixture to reflux until a clear solution was obtained. The solution was filtered while hot and the filtrate was cooled to room temperature and stirred for 10-12 hours. The crystals obtained were filtered, washed with isopropanol and dried.

CN104151290A (hereinafter referred to as CN’290 publication) discloses a new crystalline form of Bilastine characterized by an XRPD pattern having 2-theta peaks at 12.47, 14.08, 14.27, 16.29, 17.18, 18.45, 18.90, 19.74, 21.14 and 24.91 ± 0.2 degrees. The solvents used for crystallization are C_l-4 alcohols, acetone, tetrahydrofuran and dioxane in combination with water.

CN104447682A (hereinafter referred to as CN’692 publication) discloses a crystalline Bilastine with a moisture content of less than 1%, which is characterized by an XRPD pattern having 2-theta peaks at 4.62, 7.94, 10.56, 11.48, 15.72, 18.45, 21.78, 22.94, 24.76, 25.34, 25.74, 26.12, 27.04, 27.58, 29.98, 32.00, 34.22 and 35.57 ± 0.2 degrees.

CN104447683A (hereinafter referred to as CN’683 publication) discloses crystalline Bilastine monohydrate with a moisture content of 3.62%-3.84% which is characterized by an XRPD pattern having 2-theta peaks at 8.04, 9.06, 10.34, 12.28, 14.16, 15.02, 17.39, 19.02, 20.00, 22.56, 24.25, 26.85, 30.74, 31.43, 32.96, 35.38, 37.42, 39.18 and 39.92 ± 0.2 degrees.

However, the processes described in the aforementioned prior art have failed to consistently produce pure crystalline form 2 of Bilastine essentially free of other polymorphic forms. The prior art processes suffer from several disadvantages such as lack of reproducibility, use of excess quantities of solvents, cumbersome and tedious processes, formation of mixture of crystalline forms, formation of different and undesired crystalline forms.

A need still remains for simple, cost effective, consistently reproducible and environmentally friendly processes for preparing highly pure crystalline Form 2 of Bilastine which is essentially free of other crystalline forms.

SUMMARY OF THE INVENTION

Extensive research and experimentation has been carried out by the present inventors to produce highly pure crystalline Form 2 of Bilastine essentially free of other crystalline forms. As a result, the present inventors have unexpectedly found that highly pure crystalline Form 2 of Bilastine essentially free of other crystalline forms can be consistently produced by a process comprising providing a clear solution of Bilastine in methanol at reflux temperature (wherein the quantity of methanol solvent required for complete dissolution of the Bilastine at reflux temperature to form a clear solution is at least 19 times with respect to the quantity of Bilastine used), optionally subjecting the clear solution to carbon treatment at reflux temperature, cooling the resulting solution at a temperature of below about 35°C to cause crystallization, stirring the resulting mass at the same temperature for at least 20 minutes, and then collecting the highly pure crystalline Form 2 of Bilastine by filtration or centrifugation.

Provided herein is a simple, cost effective and consistently reproducible process for the preparation of highly pure crystalline Form 2 of Bilastine essentially free of other crystalline forms.

In another aspect, provided herein is a pharmaceutical composition comprising highly pure crystalline Form 2 of Bilastine essentially free from other crystalline forms made by the process disclosed herein, and one or more pharmaceutically acceptable excipients.

In still further aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form 2 of Bilastine essentially free of other crystalline forms made by the process disclosed herein with one or more pharmaceutically acceptable excipients. In another aspect, the highly pure crystalline Form 2 of Bilastine essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D₉₀ particle size of less than or equal to about 150 microns, specifically about 1 micron to about 110 microns, and most specifically about 4 microns to about 90 microns.

As used herein, the term“reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.

The term “crystalline Form 2 of Bilastine”, otherwise called “Bilastine crystalline Form 2”, as used herein is intended to mean the crystalline form 2 of Bilastine as originally disclosed in the U.S. Patent No. 7,612,095.

In one embodiment, the crystalline Form 2 of Bilastine essentially free of other crystalline forms obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 9.32, 9.62, 12.82, 14.90, 16.14, 17.78 and 21.37 ± 0.2 degrees substantially in accordance with Figure 1; an infra red (FT-IR) spectrum having main bands at about 3052, 2969, 2933, 2869, 2801, 1694, 1614, 1505, 1457, 1430, 1379, 1352, 1328, 1255, 1198, 1155, 1122, 1048, 995, 974, 834, 743 and 627 cm ¹ ± 5 substantially in accordance with Figure 2; and a Differential Scanning Calorimetric (DSC) thermogram having a sharp endo therm peak at about 205 °C substantially in accordance with Figure 3.

In one embodiment, the crystalline Form 2 of Bilastine obtained by the processes disclosed herein is essentially free from other solid state forms of Bilastine detectable by the spectral methods typically used, e.g., Powder X-ray diffraction.

The term“crystalline Form 2 of Bilastine essentially free of other crystalline forms” means that no other polymorphic forms of Bilastine can be detected within the limits of a powder X-ray diffractometer. The term“other polymorphic forms of Bilastine” is intended to mean the polymorphic forms of Bilastine other than crystalline Form 2.

The process disclosed herein above advantageously produces the crystalline Form 2 of Bilastine with high chemical and polymorphic purity.

The highly pure crystalline Form 2 of Bilastine obtained by the process disclosed herein has a chemical purity of greater than about 99.5%, specifically greater than about 99.7%, and most specifically greater than about 99.9% as measured by HPLC.

Unless otherwise specified, the term“crude or impure form of Bilastine” refers to any form of Bilastine having purity less than about 99.5% as measured by HPLC.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of crystalline Form 2 of Bilastine.

Figure 2 is a characteristic infra-red (IR) spectrum of crystalline Form 2 of Bilastine. Figure 3 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of crystalline Form 2 of Bilastine.

DETAIFED DESCRIPTION OF THE INVENTION

According to one aspect, there is provided a process for the preparation of a stable and highly pure crystalline Form 2 of Bilastine essentially free of other crystalline forms, comprising:

a) providing a solution of Bilastine in methanol at reflux temperature, wherein the quantity of methanol solvent required for complete dissolution of the Bilastine to form a clear solution at reflux temperature is at least 19 times with respect to the quantity of Bilastine used;

b) optionally, subjecting the solution obtained in step-(a) to carbon treatment at reflux temperature to obtain a filtrate;

c) cooling the solution obtained in step-(a) or step-(b) at a temperature of below about 35°C to cause crystallization; and

d) collecting the highly pure crystalline Form 2 of Bilastine essentially free of other crystalline forms formed in step-(c).

The present inventors have surprisingly and unexpectedly found that the quantity of methanol solvent with respect to the quantity of Bilastine employed is critical in order to consistently produce the highly pure crystalline Form 2 of Bilastine essentially free of other crystalline forms. In one embodiment, the amount of methanol solvent employed in step-(a) is about 19 times (volumes) to about 25 times (volumes), most specifically about 20 times with respect to the quantity of Bilastine used.

Step-(a) of providing a solution of Bilastine includes dissolving Bilastine (crude or pure) in methanol at reflux temperature, or obtaining an existing solution from a previous processing step.

In one embodiment, the Bilastine is dissolved in methanol at the reflux temperature. After complete dissolution of Bilastine, the resulting solution is stirred at the reflux temperature for at least 10 minutes, and specifically for about 20 minutes to about 30 minutes.

The carbon treatment in step-(b) is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon at the reflux temperature for at least 5 minutes, specifically for about 10 minutes to about 30 minutes, and filtering the resulting mixture through charcoal bed to obtain a filtrate containing Bilastine by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.

In one embodiment, the crystallization in step-(c) is accomplished by cooling the solution while stirring at a temperature of about 0°C to about 30°C for at least 20 minutes, and more specifically at a temperature of about l0°C to about 20°C for about 30 minutes to about 2 hours.

The collection of the precipitated solid in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.

In one embodiment, the highly pure crystalline Form 2 of Bilastine, obtained by the process described herein, remains in the same crystalline form and is found to be stable, when stored at a temperature of about 25±2°C and at a relative humidity of about 55+5%, for a period of at least 2 years.

In one embodiment, the crystalline Form 2 of Bilastine essentially free of other crystalline forms obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 9.32, 9.62, 12.82, 14.90, 16.14, 17.78 and 21.37 + 0.2 degrees substantially in accordance with Figure 1; an infra red (FT-IR) spectrum having main bands at about 3052, 2969, 2933, 2869, 2801, 1694, 1614, 1505, 1457, 1430, 1379, 1352, 1328, 1255, 1198, 1155, 1122, 1048, 995, 974, 834, 743 and 627 cm ¹ ± 5 substantially in accordance with Figure 2; and a Differential Scanning Calorimetric (DSC) thermogram having a sharp endo therm peak at about 205 °C substantially in accordance with Figure 3.

In another embodiment, the highly pure crystalline Form 2 of Bilastine obtained by the process disclosed herein is further characterized by an X-ray powder diffraction pattern having additional 2-theta peaks at about 6.48, 10.95, 13.58, 15.75, 18.43, 18.89, 20.11, 22.01 and 22.41 ± 0.2 degrees substantially in accordance with Figure 1.

The highly pure crystalline Form 2 of Bilastine obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rotavapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.

Preferably, the drying is carried out at atmospheric pressure at temperatures such as about 50°C to about 80°C and most preferably at about 50°C to about 65°C. In one embodiment, the drying is carried out for any desired time period that achieves the desired result, preferably for a period of about 1 hour to 20 hours, and more preferably about 14 to 18 hours. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.

Unless otherwise specified, the Bilastine as used herein as starting material can be obtained by the processes known in the prior art, for example, as per the processes described in the U.S. Patent No. 5,877,187 or the pending PCT Application No. PCT/IB2017/055146 filed by the present applicant.

The stable and highly pure crystalline Form 2 of Bilastine obtained by the processes disclosed herein is free from other crystalline forms, which has very good flow properties and is consistently reproducible, and is found to be more stable. The crystalline Form 2 of Bilastine obtained by the processes disclosed herein exhibits properties making it suitable for formulating Bilastine.

Further encompassed herein is the use of the highly pure crystalline Form 2 of Bilastine obtained by the processes disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.

A specific pharmaceutical composition of highly pure crystalline Form 2 of Bilastine obtained by the processes disclosed herein is selected from a solid dosage form and an oral suspension.

In one embodiment, the highly pure crystalline Form 2 of Bilastine obtained by the processes disclosed herein, for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 150 microns, specifically about 1 microns to about 110 microns, and most specifically about 4 microns to about 90 microns.

In another embodiment, the particle sizes of the highly pure crystalline Form 2 of Bilastine obtained by the processes disclosed herein are accomplished by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.

The term“micronization” used herein means a process or method by which the size of a population of particles is reduced.

As used herein, the term“micron” or“pm” both are equivalent and refer to “micrometer” which is lxl(T⁶ meter.

As used herein, “crystalline particles” means any combination of single crystals, aggregates and agglomerates.

According to another aspect, there are provided pharmaceutical compositions comprising highly pure crystalline Form 2 of Bilastine obtained by the processes disclosed herein and one or more pharmaceutically acceptable excipients.

According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form 2 of Bilastine obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients. Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of highly pure crystalline Form 2 of Bilastine obtained by the processes disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, lozenges, elixirs and the like.

The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinbelow.

Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS:

X-Ray Powder Diffraction (P-XRD):

The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Ka radiation). Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 0.4 seconds. The sample was simply placed on the sample holder. The instrument is operated at a voltage 40 KV and current 35 mA. Infra-Red Spectroscopy (FT-IR):

FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the production of the KBr compacts approximately 2 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm ¹ to 650 cm ¹.

Differential Scanning Calorimetry (DSC):

Differential Scanning Calorimetry (DSC) measurements were performed with a Differential Scanning Calorimeter (DSC Q200, Q Series Version-2.7.0.380, TA Instruments-Waters LLC) equilibrated at 50°C and Ramp at a scan rate of l0°C per minute to 250°C.

HPLC Method for measuring Chemical Purity:

The chemical purity was measured by HPLC system with UV detector or its equivalent under the following conditions: Column = Unison UK Cl 8, 250 mm x 4.6 mm, 3pm; Detector wavelength = 220 nm; Flow Rate = 1.2 ml/minute; Injection volume = 10 pL; Oven temperature = 30°C; Run time = 70 minutes; Diluent = Methanol; Elution = Gradient; and Sample Concentration: 1.0 mg/ml.

Mobile Phase-A: A mixture of buffer and Acetonitrile 90:10 (v/v)

Mobile Phase-B: A mixture of buffer and Acetonitrile 17:83 (v/v)

The following example is given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES

Example 1

Preparation of pure crystalline Form 2 of Bilastine

Methanol (200 ml) was added to crude Bilastine (10 g, Purity by HPLC: 99.2%) at 25- 30°C and the resulting suspension was heated to reflux temperature to form a clear solution, and then stirred for 20 to 30 minutes at reflux temperature. Carbon powder (1 g) was added to the resulting solution at reflux temperature and then stirred for 10 minutes at the same temperature. The reaction mixture was filtered through charcoal bed and washed the bed with hot methanol (10 ml). The resulting filtrate was cooled to l0-20°C, followed by stirring the mass for 30 minutes at the same temperature. The separated solid was filtered, washed the solid with chilled methanol (10 ml) and then dried the material at 55-60°C for 14 to 18 hours to produce 8.4 g of pure crystalline Form 2 of Bilastine (Purity by HPLC: 99.7%).

Example 2

Preparation of pure crystalline Form 2 of Bilastine

Methanol (200 ml) was added to crude Bilastine (10 g) at 25-30°C and the resulting suspension was heated to reflux temperature to form a clear solution, and then stirred for 20 to 30 minutes at reflux temperature. The resulting solution was cooled to 10- 20°C, followed by stirring the mass for 30 minutes at the same temperature. The separated solid was filtered, washed the solid with chilled methanol (10 ml) and then dried the material at 55-60°C for 14 to 18 hours to produce 9 g of pure crystalline Form 2 of Bilastine.

Example 3

Preparation of pure crystalline Form 2 of Bilastine

Methanol (200 L) was added to crude Bilastine (10 kg, Purity by HPLC: 99.5%) at 25- 30°C and the resulting suspension was heated to reflux temperature to form a clear solution, and then stirred for 20 to 30 minutes at reflux temperature. Carbon powder (1 kg) was added to the resulting solution at reflux temperature and then stirred for 10 minutes at the same temperature. The resulting mixture was filtered and washed with hot methanol (10 L). The resulting filtrate was cooled to 20-25°C, followed by stirring the mass for 30 minutes at the same temperature. The separated solid was filtered, washed the solid with chilled methanol (20 L) and then dried the material under vacuum at 55-60°C for 22 to 24 hours to produce 8 kg of pure crystalline Form 2 of Bilastine (Purity by HPLC: 99.9%).

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.

The term “pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for veterinary use and/or human pharmaceutical use.

The term“pharmaceutical composition” is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

The term“therapeutically effective amount” as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.

The term “delivering” as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host, e.g., human, animal, etc.

The term“buffering agent” as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.

The term“sweetening agent” as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.

The term“binders” as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non- aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.

The term“diluents” or“filler” as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.

The term“glidant” as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.

The term“lubricant” as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.

The term“disintegrant” as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.

The term“wetting agent” as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).

All ranges disclosed herein are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

Claims

We Claim:

1. A process for the preparation of a stable and highly pure crystalline Form 2 of Bilastine essentially free of other crystalline forms, comprising:

2. The process of claim 1, wherein the crystalline Form 2 of Bilastine essentially free of other crystalline forms obtained by the process is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 9.32, 9.62, 12.82, 14.90, 16.14, 17.78 and 21.37 ± 0.2 degrees substantially in accordance with Figure 1; an infra red (FT-IR) spectrum having main bands at about 3052, 2969, 2933, 2869, 2801, 1694, 1614, 1505, 1457, 1430, 1379, 1352, 1328, 1255, 1198, 1155, 1122, 1048, 995, 974, 834, 743 and 627 cm ¹ ± 5 substantially in accordance with Figure 2; and a Differential Scanning Calorimetric (DSC) thermogram having a sharp endotherm peak at about 205°C substantially in accordance with Figure 3.

3. The process of claim 2, wherein the crystalline Form 2 of Bilastine essentially free of other crystalline forms obtained by the process is further characterized by an X- ray powder diffraction pattern having additional 2-theta peaks at about 6.48, 10.95, 13.58, 15.75, 18.43, 18.89, 20.11, 22.01 and 22.41 ± 0.2 degrees substantially in accordance with Figure 1.

4. The process of claim 1, wherein the amount of methanol solvent employed in step- (a) is about 19 times (volumes) to about 25 times (volumes) with respect to the quantity of Bilastine used.

5. The process of claim 4, wherein the amount of methanol solvent employed in step- (a) is about 20 times (volumes) with respect to the quantity of Bilastine used.

6. The process of claim 1, wherein the solution in step-(a) is prepared by dissolving Bilastine (crude or pure) in methanol at reflux temperature; and wherein the crystallization in step-(c) is accomplished by cooling the solution while stirring at a temperature of about 0°C to about 30°C for at least 20 minutes.

7. The process of claim 1, wherein the crystallization in step-(c) is accomplished by cooling the solution while stirring at a temperature of about lO°C to about 20°C for about 30 minutes to about 2 hours.

8. Highly pure crystalline Form 2 of Bilastine essentially free of other crystalline forms, characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 9.32, 9.62, 12.82, 14.90, 16.14, 17.78 and 21.37 ± 0.2 degrees substantially in accordance with Figure 1; an infra red (FT- IR) spectrum having main bands at about 3052, 2969, 2933, 2869, 2801, 1694, 1614, 1505, 1457, 1430, 1379, 1352, 1328, 1255, 1198, 1155, 1122, 1048, 995,

974, 834, 743 and 627 cm ¹ ± 5 substantially in accordance with Figure 2; and a Differential Scanning Calorimetric (DSC) thermogram having a sharp endotherm peak at about 205 °C substantially in accordance with Figure 3.

9. A pharmaceutical composition comprising highly pure crystalline Form 2 of Bilastine essentially free of other crystalline forms, wherein the crystalline Form 2 of Bilastine has a D₉₀ particle size of less than or equal to about 150 microns.

10. The pharmaceutical composition of claim 9, wherein the crystalline Form 2 of Bilastine has a D₉₀ particle size of about 1 micron to about 110 microns.