Indian Patents. 213637:POLYMORPH 1 OF BILASTINE, PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITION COMPRISING IT.

Title of Invention	POLYMORPH 1 OF BILASTINE, PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITION COMPRISING IT.
Abstract	The invention discloses a polymorph 1 of bilastine characterised by X-ray crystallography data and an infrared spectrum in potassium bromide and a composition thereof.

Full Text	1 POLYMORPH 10F BILASTINE, PROCESS FOR ITS PREPARATION AND PHARMACEUTICA Area of the invention The invention refers to a new polymorphous crystalline form of 4-[2-[4-[1-(2-ethoxyethyl)-1H-ben2imidazole-2-yl]-1-piperidinyl]ethyl]-aa-dimethyl-benzene-acetic acid (herein referred to as "bilastine") of formula (I). From hereon referred to as polymorph 1, to procedures used to prepare it, to pharmaceutical formulae that contain polymorph 1 and to the use of polymorph 1 to treat allergic reactions and pathological processes mediated by histamine in mammals, such as man. Background of the Invention US patent number 5,877,187 confers the rights to bilastine, a preparation with antihistaminic properties without sedative or cardiovascular effects. This patent also concerns a procedure to prepare bilastine and the use of this preparation to treat allergic reactions in mammals but it does not include or suggest the possible existence of polymorphic forms of this compound. 2 To prepare pharmaceutical preparations containing bilastine for their administration in mammals and especially in man, in accordance with international health authority specifications, bilastine must be manufactured in the most stable crystalline form possible, especially in a form that has constant physical properties. Summary of the Invention We have found that bilastine can exist in three different crystalline polymorphic forms, each with different physical properties. The invention refers to a pure crystalline form of polymorph 1 of bilastine, characterised by X-ray crystallographic analysis, with approximate crystal parameters as follows: Crystallographic system Monoclinic Spatial group P2(1)/c Crystal size 0.56 x 0.45 x 0.24 mm Cell dimension a=23.38 (5) A angstrom = 90° b=8.829(17)A =90° c=12.59(2)A Y = 90° Volume 2600 A3 Z, calculated density 4, 1.184 mg/m3 The crystalline polymorph 1 of bilastine is also characterised by its infrared absorption spectrum. in potassium bromide tablet that has the following characteristic absorption bands, expressed in reciprocal centimetres: 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), * where (w) = weak intensity, (m)= medium intensity, (s) = strong intensity, (vs) = very strong intensity. Figure 1 represents the infrared spectrum of the crystalline polymorph 1 of the biiastine in a potassium bromide tablet recorded in a Perkin Elmer Spectrum One FTIR spectrophotometer. Brief description of the figures Figure 1 shows a typical infrared absorption spectrum in potassium bromide of poiymorph 1. (Vertical axis: Transmission (%); Horizontal axis: Wavenumber (cm-1)). Figure 2 shows a typical infrared absorption spectrum in potassium bromide of poiymorph 2. (Vertical axis: Transmission (%); Horizontal axis: Wavenumber (cm-1)). Figure 3 shows a typical infrared absorption spectrum in potassium bromide of poiymorph 3. (Vertical axis: Transmission (%); Horizontal axis: Wavenumber (cm-1)). Detained description of the invention We have found that bilasfine can exist in three clearly different polymorphic forms called polmorph 1, poiymorph 2 and poiymorph 3. -3A- The procedure described in US patent no. 5,877,187 generates a mixture of polymorphs 2 and 3 which corresponds to crude bilastine. More in particular, crude bilastine is prepared by hydrolysis of the corresponding benzimidazole (l-(2-ethoxyethyl)-2-[l-(2-(4-(l-(4,4-dimethyl-A2-oxazoline-2-yl)-l-methylethyl) phenyl)-ethyl)piperidme-4-yl]-lH-benzimidazole (la)) with a mineral acid such as HC1 (example 2) or H2SO4. The bilastine so obtained is a crude product having a melting point of 199-201 °C, being the melting point of pure polymorph 2 of 205.2 °C and that of pure polymorph 3 of 197 °C, so that crude bilastine is a mixture of polymorphs 2 and 3 but it does not consist of pure polymorph 2, pure polymorph 3 or a mixture of said pure polymorphs. The inventors of the present invention have discovered experimental conditions and specific solvents to produce clearly different polymorphic forms of bilastine. The crystalline polymorph 1 of pure bilastine is prepared according to the procedures of this invention. The polymorphic forms 1 is most stable at the three isomers and this makes it an ideal candidate for drug formulation. Polymorph 3 is not stable and is difficult to obtain in the pure form. Both polymorph 2 and polymorph 3 are converted into polymorph 1 by the procedures of this invention. 4 Polymorph 3 is not very stable and is difficult to obtain in the pure form. Both polymorph 2 and polymorph 3 are converted into polymorph 1 by the procedures of this invention. Polymorph 1 of bilastine has a melting point of 200.3°C. Polymorph 2 has a melting point of 205.2°C. Polymorph 3 has a melting point of 197.0°C. The crystalline polymorphic form 1 of bilastine is also characterised by its infrared absorption spectrum in potassium bromide that has the following characteristic absorption bands, expressed in reciprocal centimetres: 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), * where (w) = weak intensity, (m)= medium intensity, (s) = strong intensity, (vs) = very strong intensity. Figure 1 represents the infrared spectrum of the crystalline polymorph 1 of the bilastine in a potassium bromide tablet recorded in a Perkin Elmer Spectrum One FTIR spectrophotometer. The crystalline polymorphic form 2 of bilastine is also characterised by its infrared absorption spectrum in potassium bromide that has the following characteristic absorption bands, expressed in reciprocal centimetres: 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 (w); 630 (w), where (w) = weak intensity, (m)= medium intensity, (s) = strong intensity, (vs) = very strong intensity. Figure 2 represents the infrared 5 spectrum of the crystalline polymorph 2 of bilastine in a potassium bromide tablet recorded in a Perkin Elmer Spectrum One FTIR spectre-photometer. The crystalline polymorphic form 3 of bilastine is also characterised by its infrared absorption spectrum in potassium bromide that has the following characteristic absorption bands, expressed in reciprocal centimetres: 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), * where (w) = weak intensity, (m) = medium intensity, (s) = strong intensity, (vs) = very strong intensity. Figure 3 represents the infrared spectrum of the crystalline polymorph 3 of the bilastine in a potassium bromide tablet recorded in a Perkin Elmer Spectrum One FTIR spectrophotometer. We have discovered that, under selected experimental conditions, the mixture of the polymorphic forms 2 and 3, obtained according to US patent no. 5,877,187, is surprisingly transformed into polymorph 1. We have also discovered that polymorph 1 of bilastine is very stable and is not transformed into any of the other polymorphs 2 and 3. Similarly, under the same experimental conditions, the pure polymorphic form 2 of bilastine is surprisingly transformed into the pure polymorphic form 1. Polymorphic form 3, which is the most unstable, undergoes the same transformation under the same conditions. Polymorph 1 of bilastine is a very stable polymorph at room temperature and is, therefore, very useful as an active ingredient of a pharmaceutical preparation. Polymorph 1 is also stable when stored at temperatures above room temperature. 6 The polymorphic crystalline form 1 of bilastine is characterised by the following data of its X-ray crystallographic analysis as a monocrystal, with crystal parameters of approximately the following values: Crystallographic system Monoclinic Spatial group P2 (1)/c Crystal size 0.56 x 0.45 x 0.24 mm Cell dimension a=23.38 (5) A angstrom = 90° b=8.829(17)A =90° c=12.59(2)A Y = 90° Volume 2600 A3 Z, calculated density 4, 1.184 mg/m3 During the development of polymorph 1 of bilastine for pharmaceutical preparations, elaborated according to correct manufacturing procedures, we have discovered that crystallization of bilastine (prepared according to the description given in US patent no. 5,877,187) from short chained alcohols, preferably isopropylic alcohol and n-butanol and mixtures thereof, leads to generation of the pure polymorphic form 1 of bilastine with a high yield. Crystallisation from acetone, dimethylsulphoxide, dimethylformamide, acetonitrile and tetrahydrofurane or mixtures thereof also lead to generation of polymorph 1, although with lower yields. It is, therefore, preferable to use the former solvents. The infrared spectrum of polymorph 1 of bilastine in potassium bromide is characterised by the following bands, absent from polymorphs 2 and 3: Wavenumber(cm-1) 3057 2929 2883 7 2857 2797 1667 1481 1431 1346 1326 1288 973 945 829 Figure 1 shows the complete infrared spectrum of polymorph 1 of bilastine in potassium bromide, recorded with a Perkin Elmer Spectrum One FTIR spectrophotometer. Pharmaceutical preparations Pharmaceutical preparations of this invention can contain, as well as an effective quantity of polymorph 1 of bilastine as an active ingredient as an antiallergic or antihistaminic agent, several pharmaceutically acceptable excipients that can be solid or liquid. The solid pharmaceutical preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid excipient can be one of several substances that act as diluents, aromatising agents, agglutinants or disintegrating agents and an encapsulation material. The powders and tablets preferentially contain from approximately 5 to approximately 20 per cent of the active ingredient. Appropriate solid excipients are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylceliulose, sodium carboxymethylcellulose, waxes with low melting point, cocoa butter and similar products. The term "preparations" includes 8 the formulation of the active ingredient with an excipient for encapsulation to produce a capsule in which the active ingredient (with or without other excipients) is surrounded with the excipient by an encapsulation material. Tablets, powders, cachets and capsules can be used as suitable forms for oral administration. The active ingredient can also be incorporated into a chewing gum that can contain sweeteners, flavorings and colorings as appropriate. To prepare suppositories, a compound with a low melting point, such as a mixture of fatty acid glycerides or cocoa butter, is melted and the active ingredient is mixed well and homogeneously dispersed in the mixture with agitation. The homogeneous melted mixture is placed in the appropriate moulds and left to cool until it solidifies. Liquid preparations include suspensions, solutions and emulsions. An example of these corresponds to aqueous suspensions that can be made by mixing the finely divided active ingredient in water with suspension agents. Aqueous solutions can be prepared by placing the active ingredient in water and adding suitable coloring agents, aromas, stabilising agents, sweeteners, solubilising and thickening agents as appropriate. Also, topical preparations are considered for nasal, ophthalmic and dermal use. Appropriate formulae for nasal administration can correspond to solutions or suspensions. Ophthalmic formulae can be solutions, suspensions or ointments. Dermal preparations can be solutions, suspensions, ointments and creams. Ointments usually contain lipophylic excipients such as mineral oil or vaseline. Solutions for ophthalmic use can contain sodium chloride, acid and/or base to adjust the pH, and purified water and preservatives. 9 Similarly, a compound is being contemplated for transdermic use, consisting of a therapeutically effective amount of active ingredient incorporated into an excipient that corresponds to a liquid, a gel, a solid matrix or an adhesive patch sensitive to pressure, to be released via a transdermic administration system. The effective antiallergic or antihistaminic amount of polymorph 1 of bilastine for topical administration varies between 0.1 and 5% of the total weight of the pharmaceutical compound. The preferred amount ranges from 0.1 to 2% of the total weight of the pharmaceutical compound. The effective antiallergic or antihistaminic amount of polymorph 1 of bilastine for oral administration varies from 1 to 50 mg/day, with preferably an amount corresponding to approximately 2 to 20 mg/day in a single or fractionated doses. Polymorph 1 of bilastine has antihistaminic. properties that have been demonstrated in experimental pharmacological models, such as preventing histamine-induced lethality in the guinea-pig and antagonism against cutaneous capillary permeability induced by histamine in the rat. The following examples illustrate but do not limit the scope of the present invention. EXAMPLE 1 Preparation of polymorph 1 of bilastine. Dissolve bilastine (see the US patent no. 5,877,187) in isopropylic alcohol heated to reflux for approximately 15-20 minutes under nitrogen while stirring. Cool the solution to 50°C over 6 hours and stop stirring. Let the solution cool to room temperature and stir again for three hours, filter and 10 wash with cold isopropylic alcohol. Dry the solid residue in a vacuum oven at 35-40°C to constant weight. EXAMPLE 2 Preparation of polymorph 1 of bilastine. Heat a suspension of bilastine (see US patent no. 5,877,187) in n-butanol and reflux for 3 hours under nitrogen while stirring. Leave the solution to cool while stirring, filter off the solid residue and dry it in a vacuum oven at 35-40°C to constant weight. EXAMPLE 3 Preparation of polymorph 1 of bilastine. Treat a mixture of polymorphs 2 and 3 of bilastine for several hours with hot acetone. Let the mixture cool to room temperature and filter off the solid residue. Dry it to constant weight. EXAMPLE 4 Preparation of polymorph 1 of bilastine. Dissolve polymorph 3 of bilastine in isopropylic alcohol heated to reflux and stir for approximately 15-20 minutes under nitrogen. Let the solution reach room temperature constantly stirring, filtering and washing with cold isopropanol. Dry the solid in a vacuum oven at 35-40°C to constant weight. EXAMPLE 5 Preparation of polymorph 1 of bilastine. Dissolve polymorph 2 of bilastine in n-butanol heated to reflux while stirring for approximately 3 hours. Let the solution reach room temperature while stirring, filtering and draining. Dry the solid in a vacuum oven at 35-40°C to constant weight. -11- WE CLAIM : 1. Polymorph 1 of bilastine having a X-ray crystallography analysis with crystal parameters of substantially the following: Crystallographic system Spatial group Crystal size Cell dimension Volume Z, calculated density Monoclinic P2 (1)/c 0.56x0.45x0.24 mm a=23.38 (5) A angstrom a = 90° b=8.829(17)A P =90° c=12.59(2)A Y =90° 2600 A3 4, 1.184 mg/m3 and an infrared spectrum in potassium bromide with the following bands: Wave number (cm'1) 3057 2929 2883 2857 2797 1666 1481 1431 1346 1326 1288 1020 973 945 829 -12- 2. A process for preparing the polymorph 1 of bilastine, as claimed in claim 1, wherein said process comprises heating the bilastine obtained by a method herein described in a solvent selected from the group consisting of short chained alcohols, such as isopropylic alcohol and n-butanoi, acetone and mixtures thereof. 3. A process for preparing the poiymorph 1 from bilastine, as claimed in claim 1, wherein said process comprises heating polymorphs 2 and 3 of bilastine or mixtures thereof, in a solvent selected from the group consisting of short chained alcohols, such as isopropylic alcohol and n-butanol, acetone and mixtures thereof. 4. A pharmaceutical preparation consisting in an effective amount of poiymorph 1 of bilastine, as claimed in claim 1, and a pharmaceutically acceptable excipient. 5. A pharmaceutical preparation, as claimed in claim 4, wherein said preparation is useful as an antihistaminic and antiallergic medicine. The invention discloses a polymorph 1 of bilastine characterised by X-ray crystallography data and an infrared spectrum in potassium bromide and a composition thereof.

Full Text

1
POLYMORPH 10F BILASTINE, PROCESS FOR ITS PREPARATION AND PHARMACEUTICA

Area of the invention
The invention refers to a new polymorphous crystalline form of 4-[2-[4-[1-(2-ethoxyethyl)-1H-ben2imidazole-2-yl]-1-piperidinyl]ethyl]-aa-dimethyl-benzene-acetic acid (herein referred to as "bilastine") of formula (I).

From hereon referred to as polymorph 1, to procedures used to prepare it, to pharmaceutical formulae that contain polymorph 1 and to the use of polymorph 1 to treat allergic reactions and pathological processes mediated by histamine in mammals, such as man.
Background of the Invention
US patent number 5,877,187 confers the rights to bilastine, a preparation with antihistaminic properties without sedative or cardiovascular effects. This patent also concerns a procedure to prepare bilastine and the use of this preparation to treat allergic reactions in mammals but it does not include or suggest the possible existence of polymorphic forms of this compound.

2
To prepare pharmaceutical preparations containing bilastine for their administration in mammals and especially in man, in accordance with international health authority specifications, bilastine must be manufactured in the most stable crystalline form possible, especially in a form that has constant physical properties.
Summary of the Invention
We have found that bilastine can exist in three different crystalline polymorphic forms, each with different physical properties.
The invention refers to a pure crystalline form of polymorph 1 of bilastine, characterised by X-ray crystallographic analysis, with approximate crystal parameters as follows:
Crystallographic system Monoclinic
Spatial group P2(1)/c
Crystal size 0.56 x 0.45 x 0.24 mm
Cell dimension a=23.38 (5) A angstrom = 90°
b=8.829(17)A =90°
c=12.59(2)A Y = 90°
Volume 2600 A3
Z, calculated density 4, 1.184 mg/m3
The crystalline polymorph 1 of bilastine is also characterised by its infrared absorption spectrum. in potassium bromide tablet that has the following characteristic absorption bands, expressed in reciprocal centimetres:
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), * where (w) = weak intensity, (m)= medium intensity, (s) = strong intensity, (vs) = very strong intensity. Figure 1 represents the infrared spectrum of the crystalline polymorph 1 of the biiastine in a potassium bromide tablet recorded in a Perkin Elmer Spectrum One FTIR spectrophotometer.
Brief description of the figures
Figure 1 shows a typical infrared absorption spectrum in potassium bromide of poiymorph 1. (Vertical axis: Transmission (%); Horizontal axis: Wavenumber (cm-1)).
Figure 2 shows a typical infrared absorption spectrum in potassium bromide of poiymorph 2. (Vertical axis: Transmission (%); Horizontal axis: Wavenumber (cm-1)).
Figure 3 shows a typical infrared absorption spectrum in potassium bromide of poiymorph 3. (Vertical axis: Transmission (%); Horizontal axis: Wavenumber (cm-1)).
Detained description of the invention
We have found that bilasfine can exist in three clearly different polymorphic forms called polmorph 1, poiymorph 2 and poiymorph 3.

-3A-
The procedure described in US patent no. 5,877,187 generates a mixture of polymorphs 2 and 3 which corresponds to crude bilastine. More in particular, crude bilastine is prepared by hydrolysis of the corresponding benzimidazole (l-(2-ethoxyethyl)-2-[l-(2-(4-(l-(4,4-dimethyl-A2-oxazoline-2-yl)-l-methylethyl) phenyl)-ethyl)piperidme-4-yl]-lH-benzimidazole (la)) with a mineral acid such as HC1 (example 2) or H2SO4. The bilastine so obtained is a crude product having a melting point of 199-201 °C, being the melting point of pure polymorph 2 of 205.2 °C and that of pure polymorph 3 of 197 °C, so that crude bilastine is a mixture of polymorphs 2 and 3 but it does not consist of pure polymorph 2, pure polymorph 3 or a mixture of said pure polymorphs. The inventors of the present invention have discovered experimental conditions and specific solvents to produce clearly different polymorphic forms of bilastine. The crystalline polymorph 1 of pure bilastine is prepared according to the procedures of this invention. The polymorphic forms 1 is most stable at the three isomers and this makes it an ideal candidate for drug formulation. Polymorph 3 is not stable and is difficult to obtain in the pure form. Both polymorph 2 and polymorph 3 are converted into polymorph 1 by the procedures of this invention.

4
Polymorph 3 is not very stable and is difficult to obtain in the pure form. Both polymorph 2 and polymorph 3 are converted into polymorph 1 by the procedures of this invention.
Polymorph 1 of bilastine has a melting point of 200.3°C. Polymorph 2 has a melting point of 205.2°C. Polymorph 3 has a melting point of 197.0°C.
The crystalline polymorphic form 1 of bilastine is also characterised by its infrared absorption spectrum in potassium bromide that has the following characteristic absorption bands, expressed in reciprocal centimetres:
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), * where (w) = weak intensity, (m)= medium intensity, (s) = strong intensity, (vs) = very strong intensity. Figure 1 represents the infrared spectrum of the crystalline polymorph 1 of the bilastine in a potassium bromide tablet recorded in a Perkin Elmer Spectrum One FTIR spectrophotometer.
The crystalline polymorphic form 2 of bilastine is also characterised by its infrared absorption spectrum in potassium bromide that has the following characteristic absorption bands, expressed in reciprocal centimetres:
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 (w); 630 (w), * where (w) = weak intensity, (m)= medium intensity, (s) = strong intensity, (vs) = very strong intensity. Figure 2 represents the infrared

5
spectrum of the crystalline polymorph 2 of bilastine in a potassium bromide tablet recorded in a Perkin Elmer Spectrum One FTIR spectre-photometer.
The crystalline polymorphic form 3 of bilastine is also characterised by its infrared absorption spectrum in potassium bromide that has the following characteristic absorption bands, expressed in reciprocal centimetres:
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), * where (w) = weak intensity, (m) = medium intensity, (s) = strong intensity, (vs) = very strong intensity. Figure 3 represents the infrared spectrum of the crystalline polymorph 3 of the bilastine in a potassium bromide tablet recorded in a Perkin Elmer Spectrum One FTIR spectrophotometer.
We have discovered that, under selected experimental conditions, the mixture of the polymorphic forms 2 and 3, obtained according to US patent no. 5,877,187, is surprisingly transformed into polymorph 1. We have also discovered that polymorph 1 of bilastine is very stable and is not transformed into any of the other polymorphs 2 and 3. Similarly, under the same experimental conditions, the pure polymorphic form 2 of bilastine is surprisingly transformed into the pure polymorphic form 1. Polymorphic form 3, which is the most unstable, undergoes the same transformation under the same conditions.
Polymorph 1 of bilastine is a very stable polymorph at room temperature and is, therefore, very useful as an active ingredient of a pharmaceutical preparation. Polymorph 1 is also stable when stored at temperatures above room temperature.

6
The polymorphic crystalline form 1 of bilastine is characterised by the following data of its X-ray crystallographic analysis as a monocrystal, with crystal parameters of approximately the following values:
Crystallographic system Monoclinic
Spatial group P2 (1)/c
Crystal size 0.56 x 0.45 x 0.24 mm
Cell dimension a=23.38 (5) A angstrom = 90°
b=8.829(17)A =90°
c=12.59(2)A Y = 90°
Volume 2600 A3
Z, calculated density 4, 1.184 mg/m3
During the development of polymorph 1 of bilastine for pharmaceutical preparations, elaborated according to correct manufacturing procedures, we have discovered that crystallization of bilastine (prepared according to the description given in US patent no. 5,877,187) from short chained alcohols, preferably isopropylic alcohol and n-butanol and mixtures thereof, leads to generation of the pure polymorphic form 1 of bilastine with a high yield. Crystallisation from acetone, dimethylsulphoxide, dimethylformamide, acetonitrile and tetrahydrofurane or mixtures thereof also lead to generation of polymorph 1, although with lower yields. It is, therefore, preferable to use the former solvents.
The infrared spectrum of polymorph 1 of bilastine in potassium bromide is characterised by the following bands, absent from polymorphs 2 and 3:
Wavenumber(cm-1)
3057
2929
2883

7
2857
2797
1667
1481
1431
1346
1326
1288
973
945
829
Figure 1 shows the complete infrared spectrum of polymorph 1 of bilastine in potassium bromide, recorded with a Perkin Elmer Spectrum One FTIR spectrophotometer.
Pharmaceutical preparations
Pharmaceutical preparations of this invention can contain, as well as an effective quantity of polymorph 1 of bilastine as an active ingredient as an antiallergic or antihistaminic agent, several pharmaceutically acceptable excipients that can be solid or liquid. The solid pharmaceutical preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid excipient can be one of several substances that act as diluents, aromatising agents, agglutinants or disintegrating agents and an encapsulation material. The powders and tablets preferentially contain from approximately 5 to approximately 20 per cent of the active ingredient. Appropriate solid excipients are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylceliulose, sodium carboxymethylcellulose, waxes with low melting point, cocoa butter and similar products. The term "preparations" includes

8
the formulation of the active ingredient with an excipient for encapsulation to produce a capsule in which the active ingredient (with or without other excipients) is surrounded with the excipient by an encapsulation material. Tablets, powders, cachets and capsules can be used as suitable forms for oral administration. The active ingredient can also be incorporated into a chewing gum that can contain sweeteners, flavorings and colorings as appropriate.
To prepare suppositories, a compound with a low melting point, such as a mixture of fatty acid glycerides or cocoa butter, is melted and the active ingredient is mixed well and homogeneously dispersed in the mixture with agitation. The homogeneous melted mixture is placed in the appropriate moulds and left to cool until it solidifies.
Liquid preparations include suspensions, solutions and emulsions. An example of these corresponds to aqueous suspensions that can be made by mixing the finely divided active ingredient in water with suspension agents. Aqueous solutions can be prepared by placing the active ingredient in water and adding suitable coloring agents, aromas, stabilising agents, sweeteners, solubilising and thickening agents as appropriate.
Also, topical preparations are considered for nasal, ophthalmic and dermal use. Appropriate formulae for nasal administration can correspond to solutions or suspensions. Ophthalmic formulae can be solutions, suspensions or ointments. Dermal preparations can be solutions, suspensions, ointments and creams. Ointments usually contain lipophylic excipients such as mineral oil or vaseline. Solutions for ophthalmic use can contain sodium chloride, acid and/or base to adjust the pH, and purified water and preservatives.

9
Similarly, a compound is being contemplated for transdermic use, consisting of a therapeutically effective amount of active ingredient incorporated into an excipient that corresponds to a liquid, a gel, a solid matrix or an adhesive patch sensitive to pressure, to be released via a transdermic administration system.
The effective antiallergic or antihistaminic amount of polymorph 1 of bilastine for topical administration varies between 0.1 and 5% of the total weight of the pharmaceutical compound. The preferred amount ranges from 0.1 to 2% of the total weight of the pharmaceutical compound.
The effective antiallergic or antihistaminic amount of polymorph 1 of bilastine for oral administration varies from 1 to 50 mg/day, with preferably an amount corresponding to approximately 2 to 20 mg/day in a single or fractionated doses.
Polymorph 1 of bilastine has antihistaminic. properties that have been demonstrated in experimental pharmacological models, such as preventing histamine-induced lethality in the guinea-pig and antagonism against cutaneous capillary permeability induced by histamine in the rat.
The following examples illustrate but do not limit the scope of the present invention.
EXAMPLE 1
Preparation of polymorph 1 of bilastine.
Dissolve bilastine (see the US patent no. 5,877,187) in isopropylic alcohol heated to reflux for approximately 15-20 minutes under nitrogen while stirring. Cool the solution to 50°C over 6 hours and stop stirring. Let the solution cool to room temperature and stir again for three hours, filter and

10
wash with cold isopropylic alcohol. Dry the solid residue in a vacuum oven at 35-40°C to constant weight.
EXAMPLE 2
Preparation of polymorph 1 of bilastine.
Heat a suspension of bilastine (see US patent no. 5,877,187) in n-butanol and reflux for 3 hours under nitrogen while stirring. Leave the solution to cool while stirring, filter off the solid residue and dry it in a vacuum oven at 35-40°C to constant weight.
EXAMPLE 3
Preparation of polymorph 1 of bilastine.
Treat a mixture of polymorphs 2 and 3 of bilastine for several hours with hot acetone. Let the mixture cool to room temperature and filter off the solid residue. Dry it to constant weight.
EXAMPLE 4
Preparation of polymorph 1 of bilastine.
Dissolve polymorph 3 of bilastine in isopropylic alcohol heated to reflux and stir for approximately 15-20 minutes under nitrogen. Let the solution reach room temperature constantly stirring, filtering and washing with cold isopropanol. Dry the solid in a vacuum oven at 35-40°C to constant weight.
EXAMPLE 5
Preparation of polymorph 1 of bilastine.
Dissolve polymorph 2 of bilastine in n-butanol heated to reflux while stirring for approximately 3 hours. Let the solution reach room temperature while stirring, filtering and draining. Dry the solid in a vacuum oven at 35-40°C to constant weight.

-11-
WE CLAIM :
1. Polymorph 1 of bilastine having a X-ray crystallography analysis with crystal parameters of substantially the following:

Crystallographic system Spatial group Crystal size Cell dimension
Volume
Z, calculated density

Monoclinic
P2 (1)/c
0.56x0.45x0.24 mm
a=23.38 (5) A angstrom a = 90°
b=8.829(17)A P =90°
c=12.59(2)A Y =90°
2600 A3
4, 1.184 mg/m3

and an infrared spectrum in potassium bromide with the following bands:
Wave number (cm'1)
3057
2929
2883
2857
2797
1666
1481
1431
1346
1326
1288
1020
973
945
829

-12-
2. A process for preparing the polymorph 1 of bilastine, as claimed in
claim 1, wherein said process comprises heating the bilastine obtained by a
method herein described in a solvent selected from the group consisting of
short chained alcohols, such as isopropylic alcohol and n-butanoi, acetone
and mixtures thereof.
3. A process for preparing the poiymorph 1 from bilastine, as claimed in
claim 1, wherein said process comprises heating polymorphs 2 and 3 of
bilastine or mixtures thereof, in a solvent selected from the group consisting
of short chained alcohols, such as isopropylic alcohol and n-butanol, acetone
and mixtures thereof.
4. A pharmaceutical preparation consisting in an effective amount of
poiymorph 1 of bilastine, as claimed in claim 1, and a pharmaceutically
acceptable excipient.
5. A pharmaceutical preparation, as claimed in claim 4, wherein said
preparation is useful as an antihistaminic and antiallergic medicine.
The invention discloses a polymorph 1 of bilastine characterised by X-ray crystallography data and an infrared spectrum in potassium bromide and a composition thereof.

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Patent Number

213637

Indian Patent Application Number

01735/KOLNP/2004

PG Journal Number

02/2008

Publication Date

11-Jan-2008

Grant Date

09-Jan-2008

Date of Filing

16-Nov-2004

Name of Patentee

FAES FARMA S.A

Applicant Address

MAXIMO AGUIRRE 14, E-48940 LEIOA SPAN

Inventors:

#	Inventor's Name	Inventor's Address
1	ORJALES VENERO AURELIO	PASEO DEL PUERTO 24, E-48990 SPAIN
2	BORDLL MARTIN MARAVILLAS	JOAZUIN ACHUCARRO SPAIN
3	CANAL MORI GONZALO	KANDELAZUBIETA SPAIN
4	BLANCO FUETE HAYDEE	CAJA DE AHORROW SPAIN
5	LUCERO DE PABLO MARIQ LUIWQ	BASARRATE SPAIN
6	RUBIO ROYO VICTOR	BIZKERRE SPAIN.
7	MOSQUERA PESTANA RAMON	MUELLE TOMAS OLABARI SPAIN

PCT International Classification Number

C07D401/04

PCT International Application Number

PCT/ES02/00194

PCT International Filing date

2002-04-19

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	PCT/ES02/00194	2002-04-19	Spain