SK7066Y1 - Crystalline dihydrate bilastine - Google Patents

Abstract

Described are crystalline forms of bilastine of the formula (I), chemically 2[4-(2-(4-(1-(2-ethoxyethyl)-1H- benzo[d]imidazole-2-yl]-piperidine-1-yl)-ethyl)-phenyl)-2-methyl propionic acid as the dihydrate, referred to as form A and form B.

Description

The present invention relates to novel crystalline forms of bilastine of formula (I), chemically 2- (4- (2- (4- (1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) piperidine-1-one)). yl) ethyl) phenyl) -2-methylpropanoic acid in the form of a dihydrate and a process for its preparation in amorphous form.

BACKGROUND OF THE INVENTION

2-Methyl-2'-phenylpropionic acid derivatives, such as bilastine (I), have excellent antihistaminic effects and are indicated for the treatment of hay fever symptoms. Three polymorphs of bilastine 1, 2, 3 are known in the patent literature, their IR spectra are described in the KBr pellet in FAES patent WO 2003089425, and polymorph 1 is further characterized by single crystal X-ray data. Polymorphs 1 and 2 are said to be stable in this patent. Crystalline Form 1 is prepared by crystallization from isopropanol or n-butanol. Also disclosed is a process for converting polymorph 2 or a mixture of polymorphs 2 and 3 to pure polymorph 1 by recrystallization or slurrying with an organic solvent. The preparation of the polymorph mixture of the polymorph mixture 2 and 3 is reportedly described in patent EP 0818454. The preparation of polymorphs 1 and 2 was reproduced in our laboratories and compared with the IR spectra records of WO 2003089425, in addition XRPD diffraction spectra were measured for each form and published in the patent application CZ PV 2012-551.

The essence of the technical solution

The present invention relates to novel crystalline bilastine dihydrates, hereinafter referred to as Forms A and B. Dihydrate Form A is characterized by the following characteristic reflections in the X-ray powder record: 8.1; 11.5; 13.8; 17.6; 20.0; 21.1 and 23.2 ± 0.2 ° 2-theta, which were measured using CuKα radiation.

This Form A exhibits yet another characteristic reflection: 8.3; 10.9; 12.2; 18.5; 18.8; 26.2 ± 0.2 ° 2-theta.

The dihydrate form B is characterized by the following characteristic reflections in the X-ray powder record: 6.1; 9.5; 10.3; 15.2; 18.3 and 21.0 ± 0.2 ° 2-theta, which were measured using CuKα radiation.

This form B exhibits yet another characteristic reflection: 11.1; 11.5; 22.1; 22.9 ± 0.2 ° 2-theta.

This form is particularly advantageous in view of the cleaning effect and the possibility of preparing the amorphous form by drying it. The technical solution thus also describes the amorphous form of bilastine of formula (I).

Another object of the present invention is a process for preparing these forms, converting the form B dihydrate to the amorphous form, as well as the amorphous form itself. Due to the poor water solubility of bilastine alone, it has been necessary to develop a suitable method for preparing a stable amorphous form with higher solubility in body fluids. There are many methods to prepare amorphous forms of API, such as lyophilization, precipitation (mostly problematic, inhomogeneous, semi-crystalline), spray drying, and many others. Surprisingly, it has been found that a stable amorphous form of bilastine can be prepared by simply recrystallizing a mixture of forms with a certain water content from methanol or a mixture thereof with water and subsequent drying. This process for the preparation of amorphous bilastine has indisputable advantages over the above methods since it is directly associated with the process of purification and drying of the final product.

Detailed description of the technical solution

The Form A dihydrate polymorph of this invention is characterized by the XRPD powder pattern shown in Table 1 and DSC.

SK 7066 Υ1

Table 1: XRPD - characteristic diffraction

Pos. [° 2Th.] Interplanar distance [A] = 0.1 nm Rel. int. [%] 6.43 13,735 5.3 6.75 13,089 7.1 6.91 12,781 10.7 8.26 10,699 10.5 8.06 10,155 100.0 9.50 9,307 4.8 10.08 8,769 6.8 10.86 8,139 20.8 11.50 7,688 45.7 12.15 7,281 20.2 12.94 6,834 8.6 13.44 6,583 28.5 13.84 6,395 50.5 14.48 6,111 17.7 14.90 5,940 26,3 15.32 5,779 5.5 16.09 5,506 23.4 17.59 5,038 77.4 18.52 4,788 47.0 18.76 4,725 41.0 20.04 4,428 33.9 20.79 4,270 25.0 21.08 4,211 32.1 21.39 4,151 15.4 21.69 4,094 16.0 21.92 4,052 15.1 22.57 3,937 16.1 23.22 3,828 19.6 23.46 3,789 14.9 24.42 3,642 7.3 26.17 3,402 17.5 27.69 3,219 9.5 28.20 3,162 10.5 29.96 2,980 4.8 31.11 2,873 4.5

Form A:

The Form B dihydrate polymorph of this invention is characterized by the XRPD powder pattern shown in Table 2 and DSC.

Table 2: XRPD - characteristic diffraction peaks corresponding to Form B dihydrate:

Pos. [° 2Th.J Interplanar distance [A] = 0.1 nm Rel. int. [%] 5.76 15,327 15.5 6.08 14,523 29.6 9.48 9,322 100.0 10.33 8,560 39.9 11,06 7,996 25.7 11.53 7,670 20.6 12.52 7,062 11.5 13.04 6,784 8.3 14.34 6,172 10.5 15.18 5,833 16.7 16.54 5,355 8.4

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Pos. [° 2Th.J Interplanar distance [A1 = 0.1 nm Rel. int. [1% 18,30 4,845 75.5 21.04 4,219 40.2 22,09 4,021 17.3 22.94 3,874 10.9 24,06 3,696 17.2 26.03 3,420 7.3 28.32 3,149 4.8 28.92 3,085 4.9

The novel polymorph dihydrate form A is prepared by slowly acidifying the alkaline aqueous solution of bilastine and isolating the precipitated crystals. In particular, bilastine hydrochloride is dissolved in a suitable solvent in the presence of an excess of a suitable base, adjusted to pH 6-8, preferably pH 7 by addition of a suitable acid solution, cooled, the precipitated crystals are aspirated, washed and mixed in a suitable solvent and subsequently dried .

Form B dihydrate is prepared by recrystallization of crude bilastine obtained according to the procedure disclosed in patent application CZ PV 2012-551 (Scheme 1).

Scheme 1

The crude bilastine thus obtained is a mixture of several crystalline phases with a water content of 4.6-12% with a chemical purity of 99-99.50%, which is crystallized from methanol or a methanol-water mixture by dissolving hot and slowly cooling to room temperature and then to 0 to -25 ° C. The crystalline product thus obtained was identified as Form B dihydrate. Similarly, Form B dihydrate was obtained by recrystallization from an amorphous form.

Specifically, the preparation of Form B dihydrate comprises the following steps:

a) dissolving bilastine hydrochloride in a suitable solvent in the presence of an excess of a suitable base,

(b) addition of a solvent suitable for azeotropic distillation, distillation of the solvent by azeotropic distillation, phase separation and shaking of the aqueous phase with a suitable solvent, or purification with a suitable sorbent, where appropriate;

c) adjusting the pH of the aqueous phase by adding a suitable acid solution to a value of 6-8, preferably pH 7,

d) cooling, sucking off the crystals, washing and subsequent drying;

e) crystallization from a suitable solvent.

Preferably, in crystallization step e), methanol or a mixture thereof with water is used as a suitable solvent.

Alternatively, Form B dihydrate is prepared as follows:

(a) dissolving bilastine in a suitable solvent mixture;

b) distilling off some of the solvents,

c) cooling, aspirating and washing the crystals with a suitable solvent;

d) drying the crystals obtained, preferably a mixture of methanol and water is used as a suitable solvent mixture, and methanol is preferably used for washing the crystals in step c).

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: XRPD pattern of Form A dihydrate

Figure 2: XRPD pattern of dihydrate form B

Figure 3: XRPD pattern of amorphous form prepared by drying dihydrate B

Figure 4: TGA recording of Form B dihydrate

Figure 5: DSC recording of Form B dihydrate

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EXAMPLES

Example 1

The crude bilastine hydrochloride (16.8 g) obtained by hydrolyzing bilastine methyl ester hydrochloride was dissolved in aqueous sodium hydroxide solution (4.35 g, 3.0 eq NaOH in 150 mL water) while hot. After cooling to room temperature, the pH was adjusted to 7 with concentrated hydrochloric acid (35%, 6.4 mL total, 2.0 eq), the product precipitated out of solution. After cooling to 5 ° C, the crystals were filtered off, washed with cold water (2 x 50 ml), fritted on dietary ether (50 ml) and suction dried by suction air drying at RT overnight. 14.97 g (70%) of the product, Form A dihydrate (HPLC 99.32%, H ₂ O content 7.5% (KF)) was obtained. The theoretical water content for the dihydrate is 7.21%.

Example 2

To bilastine methyl ester hydrochloride (25.7 g, 50 mmol, HPLC 96.00%) in methanol (100 mL) was added aqueous sodium hydroxide solution (6 g (150 mmol, 3 eq) NaOH in 250 mL water) with stirring, and the mixture was heated to boiling (110 ° C bath) with stirring under nitrogen. After seven hours the reaction was complete (verified by HPLC), the bath temperature was raised to 125 ° C, and the methanol was distilled off at atmospheric pressure (6565 mL). The remainder of the methanol was removed by azeotropic distillation after addition of toluene (150 ml), collected with about 50 ml of distillate. After cooling to room temperature, the biphasic mixture was shaken in a separatory funnel, the phases separated and the aqueous phase washed with toluene (2 x 100 mL) to remove non-polar impurities. Activated charcoal (2.5 g) was added to the aqueous phase and the mixture was stirred at room temperature for 2 hours.

The sorbent was removed by filtration and washed with water (20 mL), the filtrate was cooled to 5-10 ° C with stirring and the pH was adjusted to 7 by addition of aqueous HCl. The resulting product suspension was stirred for 2 h at 5-10 ° C and the crystalline product was then filtered off, washed with cold water (2 x 50 mL) and air-dried overnight. 16.8 g (73%) of crude bilastine (HPLC 99.13%, H ₂ O content 4.6%) was obtained as a mixture of polymorphs (XRPD). The product (15.0 g) was recrystallized from methanol (200 ml) at boiling - a portion of methanol (50 ml) was distilled off and the solution was cooled slowly to -4 ° C. The crystals were filtered off and washed with cold methanol (4 x 10 mL) and dried. The obtained Form B dihydrate was further dried in a vacuum oven at 40 ° C / 180 hPa for 15 h. Yield 13.8 g (92%) of the product - HPLC 99.40%, XRPD pattern corresponds to amorphous form, water content 0.4% (KF).

Example 3

The amorphous bilastine (12.3 g) was dissolved in methanol (183 ml) and water (1.2 ml) while stirring and boiling, part of the methanol was distilled off (50 ml) and the solution was slowly cooled to 0 ° C with stirring. . The crystals were filtered off and washed with cold methanol (2 x 15 mL) and air-dried for 17 h to give 12.9 g of the product, dihydrate form B (HPLC 99.58%, H ₂ O 8.3% (KF), 7, 6% (TGA), methanol content about 50 ppm (GC)). The theoretical water content for the dihydrate is 7.21%.

List of analytical methods

Diffraction patterns were measured on an X'PERT PRO MPD PANalytical diffractometer with graphite monochromator, CuKa radiation (λ = 0, 1542 nm, ie 1.542 Ä), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40 ° 2Θ, step size: 0.01 ° 2Θ. The measurement was performed on a flat powder sample with a flat / thickness of 10 / 0.5 mm. Programmable divergence irradiators with an irradiated sample area of 10 mm, Soller irons 0.02 series and anti-diffuser iris / ₄ ° were used to adjust the primary optics. To adjust the secondary optics, an X'Celerator detector with maximum aperture opening, a 0.02 row Soller, and a 5.0 mm anti-scattering aperture were used.

Differential Scanning Calorimetry (DSC) records were measured on a DSC Pyris 1 instrument from Perkin Elmer. The sample weighed into a standard Al crucible was between 3-4 mg and a heating rate of 10 ° C / min. The temperature program used was composed of 1 stabilization minute at 50 ° C and then from heating to 250 ° C at a heating rate of 10 ° C / min. The carrier gas used was 4.0 N ₂ at a flow rate of 20 ml / min.

Dynamic Vapor Sorption (DVS) records were recorded on a DVS Advantage 1 from Surface measurement systems. The sample weighed into the quartz bowl was between 15-30 mg and the temperature in the instrument was between 25-25.2 ° C. Measurement program used: The sample was loaded with two cycles having a relative humidity of 0% to 90% (sorption) and then from 90% to 0% RH (desorption). This course was repeated in the second cycle. 4.0 N ₂ was used as the carrier gas at a flow rate of 200 ml / min.

Determination of chemical purity by UPLC: Column 1 = 0.10 m, internal diameter 2.1 mm, UPLC BEH C18 (1.7 (gm), temperature 40 ° C. Mobile phase: A: phosphate buffer - 10 mM (NH _{4) 12} HPO ₄ , pH adjusted to 9.0 with aqueous NH ₄ OH, B: acetonitrile.

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Gradient elution see Table

Time (min) A% B% 0 75 25 0.5 75 25 5.5 30 70 10.5 30 70 11 75 25 12 75 25

Flow: Detection:

Analysis Time:

0.4 ml / min UV at 220 nm 10.5 min

Claims (3)

PROTECTION REQUIREMENTS Crystalline bilastine dihydrate of formula (I) exhibiting these main characteristic peaks in X-ray powder diffraction measured using 15 CuKa8.1 radiation; 11.5; 13.8; 17.6; 20.0; 21.1 and 23.2 ± 0.2 ° 2-theta. The dihydrate of claim 1 having further characteristic peaks in powder X-ray diffraction measured using CuKα radiation of 8.3; 10.9; 12.2; 18.5; 18.8; 26.2 ± 0.2 ° 2-theta. 3 drawings