SK50032014U1 - Crystalline dihydrate bilastin - Google Patents

Abstract

Described are crystalline forms of bilastine of formula (I), chemically 2- (4- (2- (4- (1- (2-ethoxyethyl) -1H-benzo [d] imidazol-2-yl) piperidin-1-yl) ethyl) ) phenyl) -2-methylpropanoic acid in the form of a dihydrate referred to as Form A and Form B.

Description

1 1 P »i (/ seo j

Bilastine Dihydrate

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

Background Art

2-Methyl-2'-phenylpropionic acid derivatives such as bilastin (I) exhibit excellent antihistaminic effects and are indicated for the treatment of hay fever symptoms. Three bilastin polymorphs 1, 2, 3 are known in the patent literature, their IR spectra are described in KBr pellet in FAES patent WO2003089425, polymorph 1 is additionally characterized by single crystal X-ray data. Polymorphs 1 and 2 are designated as 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 by stirring in suspension with an organic solvent. The preparation of a mixture of polymorphs of a mixture of polymorphs 2 and 3 is reportedly described in EP0818454. Preparations of polymorphic forms 1 and 2 were reproduced and compared with IR spectra from WO2003089425 in our laboratories, and 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 subject of the invention is the new crystalline bilastine dihydrates, hereinafter referred to as forms A and B. The dihydrate form A is characterized by these characteristic reflections in X-ray powder recordings: 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 shows yet another characteristic reflection: 8.3; 10.9; 12.2; 18.5; 18.8; 26.2 ± 0.2 ° 2-theta. 2

Dihydrate Form B is characterized by these characteristic reflections in X-ray powder recording: 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 shows 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. Thus, the technical solution also describes the amorphous form of bilastine of formula (I). Another object of the present invention is to provide 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 solubility of bilastine alone in water, it was 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 simple recrystallization of a mixture of forms with some water content of methanol or a mixture thereof with water, followed by drying. This method of preparing amorphous bilastine has undeniable advantages over the above methods because it is directly linked to the process of purification and drying of the final product.

Detailed description of the technical solution

Polymorph of the dihydrate Form A according to the present invention is characterized by the powder XRPD pattern shown in Table 1 and DSC.

Tab. 1: XRPD - characteristic diffraction peaks corresponding to the dihydrate form A:

Pos. f ° 2Th.l 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 3 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

Polymorph of dihydrate Form B according to the present invention is characterized by powder XRPD pattern as shown in Table 2 and DSC.

Tab. 2: XRPD - characteristic diffraction peaks corresponding to dihydrate form B:

Pos. f ° 2Th.l 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 18.30 4.845 75.5 4 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 new polymorph dihydrate Form A is prepared by slowly acidifying the alkaline aqueous bilastine solution and isolating the precipitated crystals. In particular, bilastine hydrochloride is dissolved in a suitable solvent in the presence of an excess of the appropriate base, the pH is adjusted to 6 to 8, preferably to pH 7 by addition of a suitable acid solution, the solution is cooled, the precipitated crystals are filtered off with suction, washed and mixed in a suitable solvent and then dried .

Dihydrate Form B is prepared by recrystallization of crude bilastine obtained according to the procedure disclosed in patent application CZ P V 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 methanol-water by dissolving hot and slowly cooling to room temperature and then to 0 to -25 ° C. The crystalline product thus obtained was identified as dihydrate form B. In a similar manner, dihydrate form B was obtained by recrystallization from an amorphous form.

In particular, the preparation of the dihydrate Form B comprises the following steps: a) dissolving bilastin hydrochloride in a suitable solvent in the presence of an excess of a suitable base, b) adding a solvent suitable for azeotropic distillation, distilling off the solvent by azeotropic distillation, phase separation and shaking the aqueous phase with a suitable solvent or purification with a suitable sorbent c) adjusting the pH of the aqueous phase by adding a suitable acid solution to 6-8, preferably pH 7, d) cooling, aspirating crystals, washing and subsequent drying, e) crystallizing from a suitable solvent. Preferably, methanol or a mixture thereof with water is used as a suitable solvent in the crystallization step e).

Alternatively, Form B dihydrate is prepared as follows: a) dissolving bilastin in a suitable solvent mixture, b) distilling off a portion of the solvents, c) cooling, aspirating and washing the crystals with a suitable solvent, d) drying the obtained crystals, preferably using a mixture of solvents methanol with water, and methanol is preferably used to wash the crystals in step c).

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1: XRPD Dihydrate Record Form A FIG. 2: XRPD record of dihydrate Form B

Fig. 3: XRPD pattern of amorphous form prepared by drying dihydrate B FIG. 4: TGA record of dihydrate Form B FIG. 5: DSC record of dihydrate Form B

Exemplary embodiments

Example 1:

The crude bilastine hydrochloride (16.8 g) obtained by hydrolysis of bilastine methyl ester hydrochloride was dissolved in an aqueous solution of sodium hydroxide (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), triturated with diethyl ether (50 mL), and suction dried at RT overnight. 14.97 g (70%) of the product, dihydrate Form A (HPLC 99.32%, H2O content 7.5% (KF)) were obtained. The theoretical water content for the dihydrate is 7.21%. 6

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) with stirring. water) and the mixture was heated to boiling (110 ° C bath) under nitrogen with stirring. After seven hours, the reaction was complete (HPLC verified), the bath temperature was increased to 125 ° C, and the methanol was distilled off at atmospheric pressure (- 65 mL). The methanol residue was removed by azeotropic distillation after the addition of toluene (150 mL), removing about 50 mL of distillate. After cooling to room temperature, the biphasic mixture was shaken, the phases separated and the aqueous phase washed with toluene (2 x 100 mL) to remove non-polar impurities. Charcoal (2.5 g) was added to the aqueous phase and the mixture 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 at 5-10 ° C for 2 h 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%, H2O content 4.6%) were obtained as a polymorph mixture (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 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. Saline 3.8 g (92%) of product was obtained - HPLC 99.40%, XRPD pattern corresponds to amorphous form, water content 0.4% (KF).

Example 3:

Bilastine in amorphous form (12.3 g) was dissolved in methanol (183 mL) and water (1.2 mL) with stirring and boiling, some 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 product, dihydrate form B (HPLC 99.58%, H2O 8.3% (KF), 7.6% (TGA), methanol content of about 50 ppm (GC)). The theoretical water content for the dihydrate is 7.21%.

List of analytical methods

Diffractograms were measured on a X'PERT PRO MPD PANalytical diffractometer with graphite monochromator, used CuKa radiation (λ = 0, 1542 nm, ie 1,542 Ä), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40 ° 20, step size: 0.01 ° 20. The measurement was carried out on a flat powder sample having a surface area / thickness of 10 / 0.5 mm. A programmable divergence screen with an irradiated sample area of 10 mm, a Soller screen of 0.02 row and an anti-scattering screen of 1 ° C were used to adjust the primary 7 optics. The X'Celerator detector with maximum detection slot opening was used to adjust the secondary optics, 0.02 rad Soller diaphragms and 5.0 mm anti-scatter diaphragm. Differential Scanning Calorimetry (DSC) records were recorded on a DSC Pyris 1 instrument from Perkin Elmer. The sample was weighed into a standard A1 crucible 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 heated to 250 ° C with a heating rate of 10 ° C / min. The carrier gas used was 4.0 N 2 with a flow rate of 20 mL / min. Dynamic Vapor Sorption (DVS) records were recorded on a DVS Advantage 1 from Surface measurement systems. The weight of the quartz sample was between 15-30 mg and the temperature in the apparatus was between 25-25.2 ° C. The measurement program that was used: the sample was loaded with two cycles having a flow rate of 0% to 90% relative humidity (sorption) and then 90% to 0% RH (desorption). This course was repeated in the second cycle. 4.0 N2 was used as the carrier gas with a flow rate of 200 ml / min.

UPLC Chemical Purity Determination: Column 1 = 0.10 m, 2.1 mm ID, UPLC BEH C18 (1.7 µm), temperature 40 ° C. Mobile phase: A: phosphate buffer - 10 mM (NH 4) 2 PO 4, pH adjusted to 9.0 with aqueous NH 4 OH, B: acetonitrile.

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 rate: Detection: Analysis time: 0.4 ml / min UV at 220 nm 10.5 min

Claims (2)

8PtV Photovoltaic Photovoltaic Coatings 1. Crystalline bilastine dihydrate of formula I ' O exhibiting these main characteristic peaks in powder X-ray diffraction measured using CuKα radiation of 8.1; 11.5; 13.8; 17.6; 20.0; 21.1 and 23.2 ± 0.2 ° 2-theta. A dihydrate according to claim 1 having additional 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.