Crystalline forms of bilastine and preparation methods thereof

专利摘要:
The invention relates to novel alpha and eta crystalline forms of 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl)ethyl]-α,α-dimethyl-benzeneacetic acid (bilastine). The invention also relates to methods for the preparation of these crystalline forms of bilastine, pharmaceutical compositions containing same and the use thereof in the treatment of histamine-mediated disease processes and allergic reactions.
公开号:ES2600827A1
申请号:ES201690068
申请日:2016-12-21
公开日:2017-02-10
发明作者:José Luis DEL RÍO PERICACHO；Maria Cristina Puigjaner Vallet；Rafael PROHENS LÓPEZ；Yolanda Esther ARREDONDO MARTÍNEZ
申请人:Urquima SA；
IPC主号:

专利说明:

DESCRIPTIONCrystalline forms of bilastine and procedures for its preparation

The present invention relates to new crystalline forms of 4- [2- [4- [1- (2-5 ethoxyethyl) -1H-benzimidazol-2-yl] -1-piperidinyl) ethyl] -α, α-dimethyl -benzenoacetic acid (bilastine), to procedures for its preparation, pharmaceutical compositions containing them and their use in the treatment of allergic reactions and pathological processes mediated by histamine.
 10
STATE OF THE TECHNIQUE

Bilastine is the international common name of 4- [2- [4- [1- (2-ethoxyethyl) -1H-benzimidazol-2-yl] -1-piperidinyl) ethyl] -α, α-dimethyl-benzeneacetic acid whose structure corresponds to the compound of formula (I):
image 1




 twenty


        (I)

Bilastine is a selective antagonist of the H1 receptors, so it is useful in the treatment of allergic reactions and pathological processes mediated by histamine, especially for the treatment of rhinoconjunctivitis and urticaria.

Bilastine as a product per se, as well as its preparation and use as an H1 receptor antagonist have been described in European patent EP0818454B1. 30

Subsequently, European patent EP1505066B1 describes three crystalline forms of bilastine. Specifically, it describes the crystalline forms 1, 2 and 3 of bilastine, which are characterized by the infrared absorption spectrum and crystallographic parameters in the case of form 1. In addition, in EP1505066B1 35
Methods for the preparation of crystalline form 1 from a mixture of crystalline forms 2 and 3 are also described. However, crystalline forms 2 and 3 of bilastine readily convert to crystalline form 1.

The different solid forms of a pharmaceutical active ingredient can have 5 different characteristics, and offer certain advantages, for example, with respect to stability, bioavailability, ease of formulation, ease of administration, among others. Since some solid forms are more suitable for one type of formulation, and other forms for other different formulations, the development of new solid forms makes it possible to improve the characteristics of the 10 pharmaceutical formulations that comprise them. In addition, depending on the therapeutic indications, one or another pharmaceutical formulation may be preferable.
 Among the especially desirable improvements of a new crystalline form of bilastine are, for example, the improvement of physicochemical properties such as stability, solubility, fluidity, sedimentation rate, malleability or compressibility, in order to facilitate its manufacture or formulation; the improvement of the pharmacokinetic properties, in order to improve its release, absorption and / or bioavailability, obtaining more constant physicochemical properties since they allow greater ease and / or flexibility in formulating. For example, the improvement of dispersibility properties 20 allows dispersion rates to be improved, especially if they are dispersed in an aqueous physiological medium, while the reduction in hygroscopicity allows the development of new routes of administration; It is also desirable to obtain stable pharmaceutical compositions under various packaging and / or storage conditions. Thus, it is especially desirable that the new solid forms of bilastine combine more than one, or even most of the advantages mentioned above.
 Therefore, there is a need to develop new solid forms, in particular, new crystalline forms of bilastine that are suitable for use in the pharmaceutical industry and, in particular, that allow for easier production of pharmaceutical compositions of bilastine in form. crystalline that meet strict pharmaceutical standards.

EXPLANATION OF THE INVENTION

The inventors have found new crystalline forms of bilastine that are stable under the conditions of preparation and storage of the pharmaceutical composition, which guarantees the reproducibility of the manufacture and the quality of the composition. These new crystalline forms of bilastine are hereinafter referred to as Alpha crystalline form and Eta crystalline form.

These properties of these new crystalline forms are especially advantageous in the case of bilastine since most solid forms of bilastine have stability problems under the usual conditions of preparation and storage of the pharmaceutical compositions containing them.

As can be seen from the data from the stability study in Table 1 of Example 9 of the present invention, the new Alpha and Eta forms are more stable under normal storage conditions and even in more extreme conditions than other forms. solids described by the inventors herein and even as stable as forms 1 and 2 and more stable than the solid form 3 of bilastine described in the state of the art. As seen in Table 1, neither degradation products of bilastine nor the transformation of the alpha 20 or Eta crystalline form into another crystalline form have been detected.

The alpha and Eta crystalline forms of the present invention not only exhibit high stability but also good physical-mechanical properties that allow them easy handling for the preparation of pharmaceutical compositions. 25

In addition, another advantage of the alpha and Eta crystalline forms of the present invention lies in the fact that it is obtained by means of a reproducible and robust preparation process that allows obtaining said crystalline forms with high yields and high richness. In addition, being hydrated forms, said process 30 requires water or mixtures of water with small amounts of organic solvents, so it is environmentally friendly, easily industrializable and economical.

According to one aspect of the present invention, an alpha crystalline form of bilastine is provided having an X-ray diffractogram comprising characteristic peaks at 8.7; 11.6; 13.4; 13.8, 14.0 and 17.7 ± 0.2 degrees 2 theta measured with an X-ray diffractometer with Cu Kα radiation (1.5418 Å).
 5
This alpha crystalline form is also characterized in that it also contains characteristic peaks at 18.6; 18.8; 20.1 and 21.1 ± 0.2 degrees 2 theta measured with an X-ray diffractometer with Cu Kα radiation (1.5418 Å). More specifically, this alpha crystalline form is also characterized in that it has an X-ray diffractogram that also includes peaks at 10.9; 12.2; 14.5; 15.0; 16.1; 17.4; 20.7; 21.4; 10 21.7; 21.9; 22.6; 23.3 and 23.5 ± 0.2 degrees 2 theta measured with an X-ray diffractometer with Cu Kα radiation (1.5418 Å).

The crystalline form of bilastine Alpha of the present invention has the X-ray diffractogram shown in FIG. 10. Said diffractogram differs from diffractograms corresponding to other forms of bilastine known in the state of the art. This new alpha crystalline form of bilastine is characterized by displaying in the X-ray powder diffractogram the pattern of peaks, expressed in units 2 theta in degrees, 2 (º), shown in the following table:
 twenty
 2 (º)  d (Å) Intensity (%)
 6.49  13.63 5.9
 6.75  13.10 4.4
 6.93  12.75 7.2
 8.29  10.67 6.4
 8.73  10.12 87.1
 10.14  8.72 5.2
 10.90  8.11 18.9
 11.56  7.65 48.1
 12.00  7.37 2.4
 12.23  7.23 15.8
 13.01  6.80 7.4
 13.45  6.58 26.0
 13.85  6.39 30.7
 13.98  6.34 37.1
 14.49  6.11 15.6
 14.63  6.05 8.6
 14.80  5.98 9.6
 15.00  5.90 18.5
 15.38  5.76 9.4
 15.87  5.58 0.7
 16.15  5.49 24.8
 16.60  5.34 6.0
 16.99  5.22 0.9
 17.44  5.08 11.7
 17.67  5.02 100
 18.04  4.92 3.3
 18.57  4.78 50.2
 18.81  4.72 46.0
 19.52  4.55 6.6
 20.10  4.42 28.3
 20.36  4.36 8.9
 20.74  4.28 20.3
 21.10  4.21 41.2
 21.41  4.15 12.5
 21.74  4.09 13.7
 21.91  4.06 10.1
 22.09  4.02 8.7
 22.37  3.97 3.0
 22.61  3.93 18.8
 22.89  3.88 3.5
 23.31  3.82 11.8
 23.48  3.79 15.4
 23.90  3.72 7.1
 24.43  3.64 9.0
 24.76  3.60 6.6
 25.01  3.56 2.7

This alpha crystalline form is a hydrated form of bilastine. The term "hydrated" refers to a compound that has water molecules that are part of its crystalline structure. Additionally, said hydrated crystalline form of the present invention may contain water molecules that are not part of the crystalline structure. As described above, this crystalline form is especially advantageous because it is stable under the conditions of preparation and storage of the pharmaceutical composition (cf. Example 9). Therefore, it is especially suitable for the preparation of a pharmaceutical composition of bilastine that meets the strict pharmaceutical standards. 10

In another embodiment of the invention, the alpha crystalline form of bilastine defined above is that which shows in the differential scanning calorimetry diagram ("Differential Scanning Calorimetry", DSC) a first broad endothermic phenomenon with a peak at 59 ° C and a heat associated 89.0 J / g; a second broad endothermic phenomenon with a peak at 111 ° C and an associated heat of 15.9 J / g followed by an exothermic phenomenon with a peak at 117 ° C and an associated heat of 43.5 J / g; a third endothermic phenomenon at 199 ° C with an associated heat of 100.4 J / g and a quarter
endothermic phenomenon at 204 ° C with an associated heat of 9.7 J / g. In another embodiment, the alpha crystalline form of the bilastine of the present invention is that which presents the DSC diagram shown in FIG. 11.

In another embodiment of the invention, the crystalline form of Bilastine Alpha 5 defined above is that which shows a weight loss of 5.9% from 30 ° C to 86 ° C in the diagram obtained by thermogravimetry analysis (TGA) . This weight loss can be attributed to the water molecules present in its crystalline structure. In another embodiment, the alpha crystalline form of the bilastine of the present invention is that which presents the TGA diagram shown in FIG. 12.

A second aspect of the present invention relates to a process for preparing the crystalline form of Bilastine Alpha defined above.
 fifteen
In one embodiment, the method of preparing the crystalline form of bilastine Alpha defined above is characterized in that it comprises a) obtaining bilastine from a suspension of bilastine form 1 in water.

In one embodiment, the process for obtaining the alpha crystalline form of bilastine (step a) is carried out with an amount of water from 6mL / g to 100 mL / g of the starting bilastine. In a preferred embodiment, the process for obtaining the alpha crystalline form (step a) is carried out with an amount of water from 20mL / g to 100 mL / g of the starting bilastine. 25

In one embodiment of the invention, the process for obtaining the alpha form bilastine (step a) comprises the following steps: a ') heating a mixture of form 1 bilastine in water at a temperature of from 40 ° C to 95 ° C; a '') cooling the suspension obtained in step a ') to room temperature; and a '' ') stir the suspension obtained in step a' ') for the period of time necessary for the transformation to occur.

In an alternative embodiment of the invention, the process for obtaining the alpha form bilastine (step a) comprises the following steps: e ') suspend bilastine 35
form 1 in water at room temperature; and e '') stir the suspension obtained in step e ') for the period of time necessary for the transformation to occur.

The term "room temperature" refers to a temperature between 5-20 ° C and 25 ° C.

Step a '') of the process for obtaining the alpha form bilastine can be carried out using any cooling technique known in the state of the art, either by contact with a cold bath or allowed to cool by removing the heat source. In another embodiment, the cooling step a '') of the preparation process of the invention is carried out for a period of time ranging from 0.5 hours to 10 hours. In another embodiment, the preparation process is characterized in that in step a '') of the process of obtaining the alpha form bilastine is carried out at a temperature of from 20 ° C to 25 ° C. fifteen

The steps a '' ') and e' ') of the process for obtaining the bilastine form Alpha can be carried out using any stirring technique known in the state of the art. In another embodiment, steps a '' ') and e' ') of the procedure for obtaining the bilastine form Alpha is carried out for a period of time from 20 24 hours to 75 hours.

In one embodiment of the invention, the process for obtaining the alpha form bilastine (step a) further comprises the following additional steps: b) Isolating the crystalline bilastine obtained in step a); and c) Separate the water from the bilastine obtained in step b).

The isolation of step b) and the removal of the solvent (water) from step c) of the process for obtaining the bilastine form Alpha can be carried out by any conventional technique known in the state of the art. For example, the isolation of step b) can be carried out by filtration, while the separation of step c) can be carried out by subsequent drying. Generally the isolation stages b) and separation c) are carried out at a temperature of from 15 ° C to 25 ° C and for a period of time from 30 minutes to 60 minutes. At temperatures above 35
Drying time is less. In another alternative embodiment, drying is carried out at a temperature of from 20 to 50 ° C; preferably under vacuum conditions.

In an alternative embodiment, the process of preparing the crystalline form 5 Alpha is a crystallization process comprising the following steps: a1) dissolving bilastine in a mixture of water and ethanol at a temperature of 75 ° C to 100 ° C; preferably at the reflux temperature of the solvent; a2) cooling the solution obtained in step a1) to a temperature from 50 ° C to 75 ° C; a3) sow the solution obtained in step a2) with the alpha crystalline form and cool the resulting solution to a temperature of 0 ° C to 25 ° C for the period of time necessary for crystallization to occur; preferably at a speed from 0.2 ° C / min to 1 ° C / min; and a3 ’) drying the crystalline form obtained in step a3) under reduced pressure at a temperature from 25 ° C to 40 ° C until the water content is comprised from 6% to 8% by weight calculated by the Karl Fischer method; preferably until the water content is about 7% by weight calculated by the Karl Fischer method.

In an alternative embodiment, the method of preparing the crystalline form 20 Alpha is a crystallization process comprising the following steps: a4) dissolving bilastine in a mixture of water, ice and a base at a temperature of from 15 ° C to 35 ° C; a5) add to the solution obtained in step a4) an aqueous acid solution to a pH from 6 to 8 for crystallization to occur; and a6) drying the crystalline form obtained in step a5) under reduced pressure at a temperature of from 25 ° C to 40 ° C until the water content is comprised from 6% to 8% by weight calculated by the Karl Fischer method; preferably until the water content is about 7% by weight calculated by the Karl Fischer method;
 30
The crystalline form of bilastine Alpha of the present invention, presents the X-ray diffractogram shown in FIG. 10; the DSC diagram shown in FIG. 11 and the TGA diagram shown in FIG. 12.

A third aspect of the present invention relates to a crystalline form called Eta characterized in that it has an X-ray diffractogram comprising characteristic peaks at 8.4; 9.6; 12.2; 13, 2; 15.1; and 19.2 ± 0.2 degrees 2 theta measured with an X-ray diffractometer with Cu Kα radiation (1.5418 Å).
 5
This crystalline form Eta is also characterized in that it also contains characteristic peaks at 19.7; 20.3; 21.5; and 23.4 ± 0.2 degrees 2 theta measured with an X-ray diffractometer with Cu Kα radiation (1.5418 Å). More specifically, this Eta crystalline form is also characterized in that it has an X-ray diffractogram that also comprises peaks at 14.0; 16.8; 17.5; 18.2 and 25.5 ± 0.2 degrees 2 10 theta measured with an X-ray diffractometer with Cu Kα radiation (1.5418 Å).

The crystalline Eta form of bilastine of the present invention has the X-ray diffractogram shown in FIG. 30. Said diffractogram differs from the diffractogram corresponding to other forms of bilastine known in the state of the art. This new Eta crystalline form of bilastine is characterized by displaying in the X-ray powder diffractogram the pattern of peaks, expressed in units 2 theta in degrees, 2 (º), shown in the following table:

 2 (º)  d (Å) Intensity (%)
 8.37  10.56 41.0
 9.55  9.26 64.9
 9.74  9.08 7.8
 11.40  7.76 4.3
 12.18  7.27 89.7
 13.19  6.71 42.1
 13.95  6.35 11.2
 15.07  5.88 52.7
 16.79  5.28 16.0
 17.49  5.07 21.0
 17.77  4.99 5.8
 18.18  4.88 22.6
 19.18  4.63 100
 19.67  4.51 26.7
 20.16  4.40 34.0
 20.34  4.37 83.9
 20.83  4.26 7.4
 21.52  4.13 25.3
 23.35  3.81 66.8
 24.26  3.67 4.9
 24.51  3.63 7.0
 24.73  3.60 6.4
 25.46  3.50 11.1

The crystalline Eta form of bilastine defined above shows in the differential scanning calorimetry (DSC) diagram a first broad endothermic phenomenon with a peak at 137 ° C and an associated heat of 35.4 J / g followed by a second endothermic phenomenon at 198 ° C with an associated heat of 13.4 J / g overlapped with an exothermic phenomenon 5 with a peak at 200 ° C and an associated heat of 14.0 J / g and followed by a third endothermic phenomenon at 204 ° C with an associated heat of 101.3 J / g. In addition, the Eta crystalline form of bilastine presents the DSC diagram shown in FIG. 31.

The crystalline Eta form of bilastine defined above shows a 10% loss of 4.0% from 30 ° C to 120 ° C in the diagram obtained by thermo gravimetric analysis (TGA). In addition, the Eta crystalline form of bilastine presents the TGA diagram shown in FIG. 32.

A fourth aspect of the invention relates to a process for preparing the crystalline form of bilastine Eta defined above.

The alpha form of the bilastine defined above can be transformed into the crystalline form Eta of the bilastine of the present invention. Thus, in one embodiment of the invention, the procedure for obtaining the Eta form bilastine is carried out from the alpha crystalline form or alternatively from a mixture of the alpha and Eta crystalline form which comprises dispersing the crystalline form in water. Alpha or alternatively a mixture of the crystalline form Alfa and Eta for a period of time necessary for the transformation to the crystalline form Eta of the bilastine of said dispersion. This procedure is advantageous because it allows obtaining the 25 Eta crystalline form of pure bilastine in high yield. In one embodiment, the time necessary for the transformation of the crystalline form Eta of the bilastine of said dispersion is from 1 to 5; preferably from 3 to 4 days.
 30
Alternatively, form 1 of the bilastine can be transformed into the crystalline form Eta of the bilastine of the present invention. Thus, in one embodiment of the invention, the
procedure for obtaining the Eta form bilastine is carried out from the crystalline form 1 which comprises dispersing the crystalline form 1 in water for a period of time necessary for the transformation to the crystalline form Eta of the bilastine of said dispersion . This procedure is also advantageous because it allows obtaining the Eta crystalline form of pure bilastine with a high yield. In one embodiment, the time necessary for the transformation of the crystalline form Eta of the bilastine of said dispersion is more than 5 days.

The term "Eta crystalline form of pure bilastine" means that no other crystalline form of bilastine is detectable by an X-ray powder diffractogram 10 measured with an X-ray diffractometer with Cu-K λ = 1.5406 Å radiation.

In one embodiment of the invention, the Eta form bilastine crystallization process comprises the following steps: i) Dissolve bilastine in a mixture of water and acetonitrile at a temperature comprised from 40 ° C to 70 ° C; ii) cooling the solution obtained in step i) to a temperature of from 25 ° C to 50 ° C; iii) sow the solution obtained in step ii) with the crystalline form Eta and cool the resulting solution to a temperature of 0 ° C to 30 ° C for the period of time necessary for crystallization to occur; and iv) drying the crystalline form obtained in step iii) under reduced pressure at a temperature ranging from 25 ° C to 40 ° C until the water content is comprised from 3.5% to 4% by weight calculated by the Karl Fischer method ; preferably the temperature is from 30 ° C to 35 ° C.

Alternatively, the Zeta form of the bilastine defined in the present invention can be transformed into the crystalline Eta form of the bilastine. Thus, in one embodiment of the invention, the procedure for obtaining the Eta form bilastine is carried out from the Zeta crystalline form which comprises maintaining said crystalline form at a temperature of from 20 ° C to 50 ° C for a period of time necessary for that the transformation to the Eta crystalline form of bilastine occurs. In one embodiment, said transformation is carried out at a reduced pressure at a temperature of from 25 ° C to 40 ° C for a period of time necessary for the transformation to the crystalline form Eta of the bilastine.

In a particular embodiment, the process for obtaining the Eta form bilastine is carried out from the Zeta crystalline form which comprises maintaining said crystalline form under reduced pressure at a temperature comprised from 25 ° C to 40 ° C; preferably from 30 ° C to 35 ° C until the water content is comprised from 3.5% and 4% by weight calculated by the Karl Fischer method.

In another particular embodiment, the procedure for obtaining the Eta form bilastine is carried out from the Zeta crystalline form which comprises maintaining said crystalline form at a temperature of from 35 ° C to 45 ° C and a relative humidity of from 65% to 80 % for a period of time necessary for the transformation to the crystalline form Eta of bilastine; preferably for a period of time longer than 2 weeks.

A fifth aspect of the invention relates to a pharmaceutical composition characterized in that it comprises a therapeutically effective amount of the alpha or Eta crystalline form of bilastine defined in the present invention, together with appropriate amounts of pharmaceutically acceptable excipients or carriers.

A "therapeutically effective amount" of the alpha or Eta crystalline form of bilastine 20 of the present invention refers to the amount of said alpha or Eta crystalline form that provides a therapeutic effect after administration.

The term "pharmaceutically acceptable" refers to excipients or carriers suitable for use in pharmaceutical technology for the preparation of the compositions for medical use. Such excipients or carriers must be pharmaceutically acceptable in the sense that they must be compatible with the rest of the ingredients of the pharmaceutical composition. They must also be suitable for use in contact with the tissues or organs of humans and animals without showing excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications in accordance with a reasonable benefit / risk ratio.

A sixth aspect of the present invention relates to the use of the alpha or Eta crystalline form of bilastine defined above, for the preparation of a medicament for the treatment of allergic reactions and pathological processes mediated by
histamine; preferably for the treatment of allergic reactions and histamine-mediated pathological processes selected from the group consisting of the symptomatic treatment of seasonal allergic rhinoconjunctivitis, the symptomatic treatment of perennial allergic rhinoconjunctivitis and the treatment of urticaria.
The inventors have found other new crystalline forms that are not known in the state of the art.

Thus, another new crystalline form of bilastine is the crystalline form that is called the Beta form and which has the X-ray diffractogram shown in FIG. 13. Said diffractogram differs from the diffractograms corresponding to other forms of bilastine known in the state of the art. This new beta crystalline form of bilastine is characterized by displaying in the X-ray powder diffractogram the pattern of peaks, expressed in units 2 theta in degrees, 2 (º), shown in the following table:
 fifteen
 2 (º)  d (Å) Intensity (%)
 3.10  29.65 48.8
 5.96  14.83 100
 9.27  9.54 44.5
 9.54  9.27 15.0
 10.08  8.77 19.9
 10.25  8.63 18.9
 10.85  8.16 10.2
 11.40  7.76 16.6
 12.34  7.17 13.8
 12.94  6.84 5.2
 14.28  6.20 7.2
 15.05  5.89 16.8
 16.03  5.53 3.8
 16.49  5.38 7.4
 16.89  5.25 7.3
 18.16  4.88 49.8
 18.94  4.68 3.3
 20.07  4.42 6.0
 20.93  4.24 23
 21.84  4.07 8.9

The beta crystalline form of bilastine defined above shows in the differential scanning calorimetry (DSC) diagram a first broad endothermic phenomenon with a peak at 76 ° C and an associated heat of 168.8 J / g followed by an exothermic phenomenon
with a peak at 99 ° C and an associated heat of 44.0 J / g. A broad exothermic phenomenon is also shown with a peak at 154 ° C and an associated heat of 13.5 J / g followed by an endothermic phenomenon at 197 ° C with an associated heat of 0.3 J / g and another endothermic phenomenon at 204 ° C with an associated heat of 103.6 J / g. In addition, the beta crystalline form of bilastine presents the DSC diagram shown in FIG. 14. 5

The beta crystalline form of bilastine defined above shows a weight loss of 7.4% from 30 ° C to 91 ° C in the diagram obtained by thermo gravimetric analysis (TGA). In addition, the beta crystalline form of bilastine presents the TGA diagram shown in FIG. 15. 10

Another new crystalline form of bilastine is what has been referred to as the Delta crystalline form and presents the X-ray diffractogram shown in FIG. 16. Said diffractogram differs from the diffractograms corresponding to other forms of bilastine known in the state of the art. This new Delta crystalline form of 15-bilastine is characterized by displaying in the X-ray powder diffractogram the pattern of peaks, expressed in units 2 theta in degrees, 2 (º), shown in the following table:
 2 (º)  d (Å) Intensity (%)
 5.28  16.75 22.5
 8.82  10.03 100
 9.07  9.75 16.4
 9.85  8.98 6.4
 10.57  8.37 24.8
 10.85  8.15 11.3
 12.55  7.05 1.5
 13.10  6.76 6.4
 13.38  6.61 37.3
 14.53  6.10 1.2
 15.88  5.58 34.8
 17.23  5.15 11.5
 17.68  5.02 16.2
 17.96  4.94 39.6
 18.54  4.78 4.9
 18.92  4.69 43.0
 19.37  4.58 46.1
 19.95  4.45 36.6
 20.25  4.38 31.7
 20.84  4.26 26.5
 21.09  4.21 21.3
 21.23  4.18 22.6
 21.98  4.04 4.1
 22.45  3.96 6.1
 23.75  3.74 1.5
 24.74  3.60 12.3
 26.65  3.34 7.0

The crystalline form of bilastine Delta defined above shows in the differential scanning calorimetry (DSC) diagram a first broad endothermic phenomenon with a peak at 63 ° C and an associated heat of 117.8 J / g followed by two endothermic phenomena overlapping at 197 ° C with a total associated heat of 101.6 J / g. In addition, the crystalline form Delta of bilastine presents the DSC diagram shown in FIG. 17.

The crystalline form of bilastine Delta defined above shows a weight loss of 3.8% from 30 ° C to 87 ° C in the diagram obtained by thermo gravimetric analysis (TGA). In addition, the crystalline form of the bilastine Delta presents the TGA diagram shown in FIG. 18.

Another new crystalline form of bilastine is the so-called epsilon crystalline form and presents the X-ray diffractogram shown in FIG. 19. Said diffractogram 15 differs from the diffractograms corresponding to other forms of bilastine known in the state of the art. This new crystalline form epsilon of bilastine is characterized by displaying in the X-ray powder diffractogram the pattern of peaks, expressed in units 2 theta in degrees, 2 (º), shown in the following table:
 twenty
 2 (º)  d (Å) Intensity (%)
 5.56  15.88 49.1
 9.16  9.65 11.1
 9.42  9.39 2.8
 10.31  8.58 3.3
 10.92  8.10 6.4
 11.11  7.96 1.7
 11.82  7.49 1.5
 12.47  7.10 1.6
 13.95  6.35 2.4
 16.18  5.48 4.5
 16.36  5.42 24.0
 16.73  5.30 23.2
 16.89  5.25 15.7
 17.38  5.10 6.5
 17.91  4.95 18.4
 18.38  4.83 100
 20.16  4.40 9.6
 20.59  4.31 6.3
 21.08  4.21 6.4
 21.55  4.12 0.6
 21.94  4.05 8.9
 22.42  3.97 1.9
 22.85  3.89 13.7
 23.17  3.84 0.7
 23.57  3.77 2.7
 24.01  3.71 1.3
 25.69  3.47 3.2

The crystalline epsilon form of bilastine defined above shows in the differential scanning calorimetry (DSC) diagram a first broad endothermic phenomenon with a peak at 81 ° C and an associated heat of 185.3 J / g followed by an exothermic phenomenon with a peak at 101 ° C and an associated heat of 48.2 J / g. Also shown is a broad exothermic phenomenon with a peak at 157 ° C and an associated heat of 14.2 J / g followed by an endothermic phenomenon at 197 ° C with an associated heat of 0.9 J / g and another endothermic phenomenon at 203 ° C with a heat associated of 111.0 J / g. In addition, the crystalline form epsilon of bilastine presents the DSC diagram shown in FIG. 20.
 10
The crystalline epsilon form of bilastine defined above shows a weight loss of 15.0% from 30 ° C to 85 ° C in the diagram obtained by thermogravimetric analysis (TGA). In addition, the crystalline form epsilon of bilastine presents the TGA diagram shown in FIG. 21.
 fifteen
Another new crystalline form of bilastine is the so-called crystalline form Gamma A and has the X-ray diffractogram shown in FIG. 22. Said diffractogram differs from the diffractograms corresponding to other forms of bilastine known in the state of the art. This new crystalline form Gamma A of bilastine is a chloroform solvate that is characterized by exhibiting in the X-ray powder diffractogram the pattern of peaks, expressed in units 2 theta in degrees, 2 (º), which is shown in the following table:

 2 (º)  d (Å) Intensity (%)
 7.00  12.62 20.6
 9.31  9.49 7.5
 10.03  8.82 50.0
 11.12  7.95 74.1
 11.96  7.40 1.9
 12.63  7.01 17.1
 13.10  6.76 5.4
 14.04  6.31 10.3
 14.21  6.23 2.2
 14.61  6.06 60.8
 15.30  5.79 9.1
 15.96  5.55 12.4
 16.64  5.33 1.5
 16.84  5.27 2.9
 17.06  5.20 16.7
 17.79  4.98 23.8
 18.09  4.90 9.4
 18.24  4.86 4.2
 18.49  4.80 0.1
 18.88  4.70 7.2
 19.15  4.64 15.3
 19.97  4.45 4.6
 20.15  4.41 2.4
 20.67  4.30 2.3
 21.12  4.21 12.9
 21.48  4.14 2.2
 21.69  4.10 7.3
 22.36  3.98 18.0
 22.58  3.94 10.5
 22.91  3.88 3.7
 23.04  3.86 5.0
 23.92  3.72 10.2
 24.21  3.68 100

The crystalline Gamma A form of bilastine defined above shows in the differential scanning calorimetry (DSC) diagram a first broad endothermic phenomenon with a peak at 80 ° C and an associated heat of 51.0 J / g followed by a second endothermic phenomenon at 201 ° C with an associated heat of 87.6 J / g. In addition, the crystalline form Gamma A of bilastine presents the DSC diagram shown in FIG. 23.

The crystalline form Gamma A of bilastine defined above shows a loss
19.0% weight from 29ºC to 90ºC in the diagram obtained by thermo gravimetric analysis (TGA). In addition, the crystalline form Gamma A of bilastine presents the TGA diagram shown in FIG. 24.

Another new crystalline form of bilastine is the crystalline form called form 5 Gamma B and has the X-ray diffractogram shown in FIG. 25. Said diffractogram differs from the diffractogram corresponding to other forms of bilastine known in the state of the art. This new crystalline form Gamma B of bilastine is a chloroform solvate that is characterized by exhibiting in the X-ray powder diffractogram the pattern of peaks, expressed in units 2 theta in degrees, 2 10 (º), which is shown in the following table:

 2 (º)  d (Å) Intensity (%)
 5.28  16.74 4.3
 9.04  9.79 53.8
 9.86  8.97 30.0
 10.13  8.73 22.2
 10.58  8.36 3.3
 11.74  7.54 6.8
 12.39  7.14 8.4
 13.12  6.75 1.2
 13.68  6.47 6.5
 15.13  5.86 3.4
 15.84  5.59 10.7
 16.33  5.43 25.7
 17.55  5.05 16.2
 18.13  4.89 8.6
 18.50  4.80 18.4
 19.07  4.65 100
 19.80  4.48 40.4
 20.52  4.33 7.0
 20.90  4.25 10.4
 21.16  4.20 22.3
 21.86  4.06 15.2
 22.68  3.92 12.4
 23.56  3.77 4.2
 23.93  3.72 1.8

The crystalline form Gamma B of bilastine defined above shows in the differential scanning calorimetry (DSC) diagram a first broad endothermic phenomenon with a peak at 82 ° C and an associated heat of 35.9 J / g followed by a
second endothermic phenomenon at 203 ° C with an associated heat of 95.1 J / g. In addition, the crystalline form Gamma B of bilastine presents the DSC diagram shown in FIG. 26.

The crystalline Gamma B form of bilastine defined above shows a weight loss of 13.0% from 29 ° C to 116 ° C in the diagram obtained by thermo gravimetric analysis (TGA). In addition, the crystalline form Gamma B of bilastine presents the TGA diagram shown in FIG. 27.

Another new crystalline form of bilastine is the crystalline form called Zeta and 10 presents the X-ray diffractogram shown in FIG. 28. Said diffractogram differs from the diffractogram corresponding to other forms of bilastine known in the state of the art. This new Zeta crystalline form of bilastine is characterized by displaying in the X-ray powder diffractogram the pattern of peaks, expressed in units 2 theta in degrees, 2 (º), shown in the following table:

 2 (º)  d (Å) Intensity (%)
 7.76  11.39 100
 8.93  9.90 34.5
 10.45  8.46 64.3
 10.63  8.32 40.0
 11.69  7.57 13.0
 12.96  6.83 38.3
 13.60  6.51 21.7
 14.65  6.05 69.9
 15.07  5.88 7.9
 15.58  5.69 21.6
 16.28  5.44 39.3
 16.53  5.36 2.5
 17.54  5.06 1.5
 18.04  4.92 11
 18.25  4.86 37.4
 18.61  4.77 0.6
 19.54  4.54 3.7
 20.38  4.36 36.8
 20.69  4.29 13.3
 21.01  4.23 1.7
 21.37  4.16 34.9
 21.73  4.09 8.5
 21.99  4.04 16.8
 22.37  3.97 60.9
 22.85  3.89 12.4
 23.10  3.85 25.1
 23.25  3.83 11.2
 23.54  3.78 5.6
 24.18  3.68 29.1
 24.37  3.65 6.9
 25.12  3.54 1.1

The crystalline form Zeta of bilastine defined above shows in the differential scanning calorimetry (DSC) diagram a first broad endothermic phenomenon with a peak at 70 ° C and an associated heat of 506.5 J / g; a second endothermic phenomenon at 198 ° C with an associated heat of 5.6 J / g overlapped with an exothermic phenomenon with a peak at 201 ° C and an associated heat of 4.6 J / g and followed by a third endothermic phenomenon with an associated heat of 100.2 J / g. In addition, the Zeta crystalline form presents the DSC diagram shown in FIG. 29.

The structure data of the Zeta crystalline form of the bilastine defined above 10 obtained by monocrystalline X-ray diffraction correspond to a pentahydrate and are shown below:

 Empirical formula  C28 H47 N3 O8
 Molecular weight  553.68
 temperature  100 (2) K
 Wavelength  0.71073 Å
 Crystalline system  monoclinic
 Space group  P 21 / c
 Unit cell parameters:  a = 11.4856 (5) Å α = 90 °. b = 8.5007 (4) Å  = 99.765 (2) °. c = 30.4880 (14) Å  = 90 °.
 volume  2933.6 (2) Å3
 Z  4
 Density (calculated)  1,254 Mg / m3
 Absorption coefficient  0.091 mm-1
 F (000)  1200
 Crystal size  0.196mmx0.250mmx0.389mm
 Theta interval  2,430 to 31,465 °.
 Index range  -16 <= h <= 16, -12 <= k <= 12, -44 <= l <= 44
 Reflections collected  100284
 Independent reflections  9660 [R (int) = 0.0553]
 Exhaustivity of theta = 25.242 °  99.9%
 Refining method  Full-matrix least-squares on F2
 Data / retention systems / parameters  9660/15/385
 Goodness-of-fit on F2  1,040
 Final indexes R [I> 2sigma (I)]  R1 = 0.0454, wR2 = 0.1043
 R indices  R1 = 0.0700, wR2 = 0.1146
 Extinction coefficient  n / a
 Major diff. spout and hole  0.432 and -0.287 e.Å-3

Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. In addition, the word "understand" includes the case "consists of". For those skilled in the art, other objects, advantages and characteristics of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention. The numerical signs relating to the drawings and placed in parentheses in a claim are only intended to increase the understanding of the claim, and should not be construed as limiting the scope of protection of the claim. In addition, the present invention covers all possible combinations of particular and preferred embodiments indicated herein.

BRIEF DESCRIPTION OF THE DRAWINGS 15

FIG. 1 shows the powder X-ray diffraction pattern (intensity (counts) vs. angle 2-theta (º)) of crystalline form 1 of bilastine known in the state of the art.
FIG. 2 shows the DSC curve of crystalline form 1 of bilastine known in the state of the art.
FIG. 3 shows the TGA diagram of crystalline form 1 of bilastine known in the state of the art.
FIG. 4 shows the powder X-ray diffraction pattern (intensity (counts) vs. 5 angle 2-theta (º)) of the crystalline form 2 of bilastine known in the state of the art.
FIG. 5 shows the DSC curve of crystalline form 2 of bilastine known in the state of the art.
FIG. 6 shows the TGA diagram of crystalline form 2 of bilastine known in the prior art.
FIG. 7 shows the powder X-ray diffraction pattern (intensity (counts) vs. angle 2-theta (º)) of the crystalline form 3 of bilastine known in the state of the art.
FIG. 8 shows the DSC curve of crystalline form 3 of bilastine known in the prior art.
FIG. 9 shows the TGA diagram of crystalline form 3 of bilastine known in the state of the art.
FIG. 10 shows the powder X-ray diffraction pattern (intensity (counts) vs. angle 2-theta (º)) of the crystalline form of bilastine Alpha of the present invention.
FIG. 11 shows the DSC curve of the alpha crystalline form of bilastine of the present invention.
FIG. 12 shows the TGA diagram of the crystalline form of bilastine Alpha of the present invention.
FIG. 13 shows the powder X-ray diffraction pattern (intensity (counts) vs. 25 angle 2-theta (º)) of the crystalline Beta form of bilastine.
FIG. 14 shows the DSC curve of the beta crystalline form of bilastine.
FIG. 15 shows the TGA diagram of the beta crystalline form of bilastine.
FIG. 16 shows the powder X-ray diffraction pattern (intensity (counts) vs. angle 2-theta (º)) of the crystalline form of bilastine Delta. 30
FIG. 17 shows the DSC curve of the crystalline form Delta of bilastine.
FIG. 18 shows the TGA diagram of the crystalline form Delta of bilastine.
FIG. 19 shows the powder X-ray diffraction pattern (intensity (counts) vs. angle 2-theta (º)) of the crystalline form epsilon of bilastine.
FIG. 20 shows the DSC curve of the crystalline form epsilon of bilastine. 35
FIG. 21 shows the TGA diagram of the crystalline form epsilon of bilastine.
FIG. 22 shows the powder X-ray diffraction pattern (intensity (counts) vs. angle 2-theta (º)) of the crystalline Gamma A form of bilastine.
FIG. 23 shows the DSC curve of the crystalline form Gamma A of bilastine.
FIG. 24 shows the TGA diagram of the crystalline form Gamma A of bilastine. 5
FIG. 25 shows the powder X-ray diffraction pattern (intensity (counts) vs. angle 2-theta (º)) of the crystalline Gamma B form of bilastine.
FIG. 26 shows the DSC curve of the crystalline form Gamma B of bilastine.
FIG. 27 shows the TGA diagram of the crystalline form Gamma B of bilastine.
FIG. 28 shows the powder X-ray diffraction pattern (intensity (counts) vs. 10 angle 2-theta (º)) of the crystalline form Zeta of bilastine.
FIG. 29 shows the DSC curve of the Zeta crystalline form of bilastine.
FIG. 30 shows the powder X-ray diffraction pattern (intensity (counts) vs. angle 2-theta (º)) of the crystalline form Eta of bilastine.
FIG. 31 shows the DSC curve of the crystalline form Eta of bilastine. fifteen
FIG. 32 shows the TGA diagram of the crystalline form Eta of bilastine.

EXAMPLES

General Considerations 20

X-ray diffractograms have been obtained using an X-ray diffractometer with Cu Kα radiation (1.5418 Å) on a PANalytical X'Pert PRO MPD powder diffractometer with a 240 mm radius, in a convergent beam configuration with a focusing mirror and a transmission geometry with flat samples 25 sandwiched between low absorbent films. The dust samples were sandwiched between 3.6 micron thick polyester films and the experimental conditions were as follows:
Radiation Cu K ( = 1.5418 Å).
Working power: 45 kV - 40 mA. 30
Incidents beam slits that define a beam height of 0.4 millimeters
Incident and diffracted slits beam 0.02 Sóller radians
PIXcel detector: active length = 3.347 º
2 /  scans from 2 to 40 º2 with a step size of 0.026 º2 and a measurement time of 76 seconds per step. 35
The diffractograms obtained show the powder X-ray diffraction pattern (intensity (counts) vs. angle 2-theta (º)).

Monocrystalline X-ray diffraction diffractions were obtained using a D8 Venture 5 monocrystalline X-ray diffraction diffractometer (SCXRD) equipped with a multilaminar monochromator and a Mo microfoco (λ = 0.71073 Å). The margins were integrated with the Bruker SAINT software using a SAINT algorithm. Data were corrected for absorption effects using a multi-scan method (SADABS). The structure was solved and refined using the Bruker SHELXTL Software Package (cf. George M. Sheldrick, Acta Cryst. (2008), A64, 112-122), a computer program for the automatic resolution of crystalline structures and refined by means of a program of a matrix-complete least squares method with ShelXle Version 4.8.0 CB Hübschle, (GM Sheldrick and B. Dittrich: a Qt graphical user interface for SHELXL (cf. J. Appl. Cryst., 44, (2011) 1281-1284), a program for refining crystalline structures.

Differential scanning calorimetry (DSC) diagrams have been obtained using a Mettler-Toledo DSC-822e calorimeter. The experimental conditions are as follows: alumina crucibles of 40 L volume, dry nitrogen atmosphere with a flow rate of 50 mL / min, heating rate of 10 ° C / min. The calorimeter was calibrated with 99.99% pure indium. DSC curves show heat fluxes (mW) vs. time and temperature. In the diagrams the exothermic phenomena are expressed upwards (˄EXO).

The diagrams by thermo gravimetric analysis (TGA) have been obtained using a Mettler-Toledo TGA-851e thermobalance equipment using 70 µl volume alumina crucibles, dry nitrogen atmosphere with 50mL / min flow rate and heating rate of 10ºC / min . The diagrams simultaneously show the variation of the mass of a sample when heated (TGA) as well as the SDTA signal expressed in milligrams (mg) vs min (minutes) and ºC (temperature). 30

The water content of the Alpha and Eta forms has been obtained by volumetric grinding according to the Karl Fischer (KFT) method, which is expressed as a percentage (%) by weight. The crystalline form Alfa was maintained at room temperature and a relative humidity of about 67% for 24 hours. 35

The measurement of the particle size of the crystalline forms 2, Alpha form and Eta form has been obtained by laser diffraction using a solid particle size Malvern model size analyzer.
 5
Comparative Example 1. Preparation of crystalline form 1 of bilastine

Method 1A
They were dissolved in 1.0 mL of ethanol, 20 mg of bilastine (0.043 mmol) at room temperature and the solvent was allowed to evaporate for 24 h. After that time, needle-shaped crystals formed and filtered. X-ray diffraction analysis gave the diffractogram shown in Fig. 1.

Method 1B
They were dissolved in 0.5 mL of methanol, 20 mg of bilastine (0.043 mmol) at 60 ° C and the solution was slowly cooled to room temperature. After 24 hours, the solid crystallized and subsequently filtered and dried under vacuum. X-ray diffraction analysis gave the diffractogram shown in Fig. 1.

Method 1C 20
They were dissolved in 1.8 mL of ethanol, 20 mg of bilastine (0.043 mmol) at 70 ° C and the solution was slowly cooled to room temperature. After 24 hours, the solid crystallized and subsequently filtered and dried under vacuum. X-ray diffraction analysis gave the diffractogram shown in Fig. 1.
 25
The water content of two different samples of crystalline form 1 obtained by this method was analyzed. The water content of these samples was 7.9% and 8.1% respectively.

1D Method 30
They were dissolved in 2.0 mL of isopropyl alcohol, 20 mg of bilastine (0.043 mmol) at 82 ° C and the solution was slowly cooled to room temperature. After 24 hours, the solid crystallized and subsequently filtered and dried under vacuum. X-ray diffraction analysis gave the diffractogram shown in Fig. 1.

The analysis of the single cell crystalline elucidation parameters of monocrystalline confirmed that the crystalline form 1 obtained by the procedures described in comparative example 1 coincided with the crystalline form 1 described in European patent EP1505066B1 of the prior art.
  5
Comparative Example 2. Preparation of crystalline form 2 of bilastine

Method 2A
In 70 µl alumina crucibles, 20 mg of the crystalline beta form of bilastine (0.043 mmol) was added and heated in a TGA device under a 10-nitrogen atmosphere where the temperature increased from 30 ° C to 198 ° C whose increase was brought to out at a rate of 10 ° C per minute. It was maintained at 198 ° C for 2 minutes and subsequently cooled to room temperature. The X-ray diffraction analysis gave the diffractogram shown in Fig. 4 and the TGA analysis shows a 0.5% weight loss between 30 ° C and 191 ° C. fifteen


Method 2B
The crystalline form 2 was prepared by reproducing the method 2A described above with 100 g of the beta crystalline form of bilastine and the product obtained was ground in a Restch ultra-centrifugal mill model ZM200 to obtain a particle size of d10 = 4.3 µm; d50 = 27.0 µm and d90 = 103 µm.

The melting point confirmed that the crystalline form 2 obtained by the procedures described in comparative example 2 (method 2A and 2B) coincided with the crystalline form 2 described in European patent EP1505066B1 of the prior art.

Comparative Example 3. Preparation of crystalline form 3 of bilastine
 30
Method 3A
They were dissolved in 0.2 mL of chloroform (CHCl3), 20 mg of bilastine (0.043 mmol) at 60 ° C and the solution was slowly cooled only by turning off the heat source to room temperature. After 6 days, the solid crystallized and
It was subsequently filtered and dried under vacuum. X-ray diffraction analysis gave the diffractogram shown in Fig. 7.

Method 3B
They were dissolved in 0.2 mL of chloroform (CHCl3), 20 mg of bilastine (0.043 mmol) at 5 60 ° C and the solution was cooled slowly by turning off the heat source and removing it from the heat source until it reached room temperature. After 6 days, the solid crystallized and subsequently filtered and dried under vacuum. X-ray diffraction analysis gave the diffractogram shown in Fig. 7.
 10
3C method
1.0 mL of diethyl ether was added at room temperature to a solution of 100 mg of bilastine (0.216 mmol) in 0.5 mL of chloroform (CHCl3). It was cooled to 0 ° C and after two hours, a white solid crystallized. Subsequently, the solid was filtered and dried under vacuum. X-ray diffraction analysis gave the diffractogram shown in Fig. 7. 15

3D method
They were suspended in 0.3 mL of chloroform (CHCl3), 50 mg of bilastine (0.108 mmol). The suspension was kept under stirring for 24 hours at room temperature. The solid crystallized and subsequently filtered and dried under vacuum. The X-ray diffraction analysis gave the diffractogram shown in Fig. 7.

3E method
They were dissolved in 0.65 mL of chloroform (CHCl3), 100 mg of bilastine (0.216 mmol) at 60 ° C and the solution was slowly cooled to room temperature. Solid 25 precipitated and subsequently filtered and dried in vacuo. The X-ray diffraction analysis gave the diffractogram shown in Fig. 7 and the TGA analysis shows a 0.7% weight loss between 33 ° C and 226 ° C.

The melting point confirmed that the crystalline form 3 obtained by the 30 procedures described in comparative example 3 coincided with the crystalline form 3 described in European patent EP1505066B1 of the prior art.

Example 1. Preparation of the crystalline form Alpha of bilastine

Method 1A
They were suspended in 2.0 mL of water, 20 mg of bilastine form 1 (0.043 mmol). The suspension obtained was heated to a temperature of 90 ° C and allowed to warm to room temperature. The suspension was allowed to stir for 72 hours at room temperature. Subsequently, the suspended solid was filtered and dried under vacuum. X-ray diffraction analysis gave the diffractogram shown in Fig. 10.

Method 1B 10
They were suspended in 2.0 mL of water, 100 mg of bilastine form 1 (0.216 mmol). The suspension obtained was heated to a temperature of 90 ° C and allowed to warm to room temperature. The suspension was allowed to stir for 72 hours at room temperature. Subsequently, the suspended solid was filtered and dried under vacuum. X-ray diffraction analysis gave the diffractogram shown in Fig. 10. 15

1C method
They were suspended in 0.6 mL of water, 100 mg of bilastine form 1 (0.216 mmol). The suspension obtained was allowed to stir for 72 hours at room temperature. Subsequently, the suspended solid was filtered and dried under vacuum. The X-ray diffraction analysis gave the diffractogram shown in Fig. 10.

1D method
250 g of Bilastine, 2.5 L of water and 1.75 L of 96 ° EtOH were charged to a reactor and heated to reflux until completely dissolved. The resulting mixture was filtered hot to a 5 L reactor, preheated previously at T = 90 ° C (if after filtration, precipitate is observed, it is reheated until the possible solid remains have dissolved).

Once all solid was dissolved, the mixture was cooled to T = 68 ° C and seeded with 30 0.25 g of Bilastine Form Alpha. The mixture was then cooled to T = 20 ° C at an approximate rate of 0.7 ° C / min. The precipitated solid was filtered and dried under vacuum at a temperature of 35 ° C until the water content was about 7% by weight (calculated by the Karl Fischer method (KFT)). 242.93 g of
a solid that corresponded with Bilastine Form Alpha with a KF: 7.4% by weight. This product obtained was ground in a Hammerwitt-LAB Valve Witt-80 Hammerwitt-LAB hammer mill, obtaining two bilastines with different particle sizes:

Bilastine form alpha 1D-a: d10 = 11.4µm; d50 = 43.7µm and d90 = 167 µm. 5
Bilastine form alpha 1D-b: d10 = 10.1µm; d50 = 31.0µm and d90 = 86.9 µm

1E method
510 mL of water, 510 g of ice, 25.5 g of potassium hydroxide (KOH) were mixed in a reactor and 169 g of Bilastine were added to this solution. It was gently heated to dissolve all the solid, filtered to a thermostated 2L reactor and washed with 340 mL of water. The mixture was heated to T = 45 ° C and a 2N HCl solution was added until the pH was adjusted to 7.2. During the pH adjustment a solid precipitated. At the end of the pH adjustment, it was maintained at T = 45 ° C for 45 min. After this time, it was cooled to a temperature between 20-25 ° C and kept stirring at this temperature for about 17 hours. The solid obtained was centrifuged and washed with 440 mL of water. The solid was drained for 30 min and dried under vacuum at T = 35 ° C until the water content was about 7% by weight (calculated by the Karl Fischer method (KFT)). The solid obtained corresponded with Bilastine Form Alpha.
 twenty
1F method
In a reactor 459.25 mL of water, 459.25 g of ice, 16.5 g of potassium hydroxide (KOH) were mixed and, over this solution 110.16 g of Bilastine were added. Once dissolved, the solid was filtered into a 2L thermostated reactor and washed with 187 mL of water and 368.5 mL of isopropanol. On this mixture at T = 23 ° C, a solution of 2N HCl was added until the pH was adjusted to 7.2. During the pH adjustment a solid precipitated. After the pH adjustment, it was kept under stirring at T = 20-25 ° C for 21 hours. The solid obtained was centrifuged and washed with 220 mL of water, drained and dried under vacuum at T = 35 ° C until the water content was around 7% by weight (calculated by the Karl Fischer method (KFT )). The solid obtained 30 corresponded with Bilastine Form Alpha.

Example 2. Preparation of the beta crystalline form of bilastine

They were suspended in 1.0 mL of methanol, 20 mg of bilastine form 1 (0.043 mmol). The suspension obtained was allowed to stir at room temperature and after 3 hours the solid in suspension was filtered and dried in vacuo. The X-ray diffraction analysis gave the diffractogram shown in Fig. 13.

Example 3. Preparation of the crystalline form Delta of bilastine

They were dissolved in 2.0 mL of dioxane, 20 mg of bilastine form 1 (0.043 mmol) at a temperature of 70 ° C. The solution obtained was allowed to cool in an ice-water bath. After 2 hours, the solution was maintained at 4 ° C for 72 hours. After this time, the precipitated solid was filtered and dried in vacuo. The X-ray diffraction analysis gave the diffractogram shown in Fig. 16.
 fifteen
Example 4. Preparation of the crystalline form Bilastine epsilon

They were dissolved in 0.55 mL of dichloromethane, 20 mg of bilastine (0.043mmol) at room temperature. Subsequently, 2.0 mL of water was added and the solution was kept at room temperature for a week. After this time, the precipitated solid was filtered and dried in vacuo. The X-ray diffraction analysis gave the diffractogram shown in Fig. 19.

Example 5. Preparation of the crystalline form Gamma A of bilastine
 25
They were dissolved in 0.2 mL of CHCl3, 50 mg of bilastine (0.106mmol) at a temperature of 60 ° C. The solution obtained was allowed to cool in an ice-water bath. After 2 hours, the solution was maintained at 4 ° C for 72 hours. After this time, the precipitated solid was filtered and dried in vacuo. X-ray diffraction analysis gave the diffractogram shown in Fig. 22. 30

Example 6. Preparation of the crystalline form Gamma B of bilastine

Method 6A
They were dissolved in 0.2 mL of CHCl3, 50 mg of bilastine (0.106 mmol) at a temperature of 60 ° C. The suspension obtained was allowed to cool in an ice-water bath. After 2 hours, the solution was maintained at 4 ° C for 12 hours. After this time, the precipitated solid was filtered and dried in vacuo. The X-ray diffraction analysis gave the diffractogram shown in Fig. 25. 5

6B method
They were dissolved in 0.5 mL of CHCl3, 20 mg of bilastine (0.043mmol) at room temperature. The solution obtained was allowed to cool in an ice-water bath. After 2 hours, the solution was maintained at 4 ° C for 12 days. After this time, the precipitated solid was filtered and dried in vacuo. The X-ray diffraction analysis gave the diffractogram shown in Fig. 25.

Example 7. Preparation of the crystalline form Zeta of bilastine
 fifteen
They were solubilized in 1.0 mL of a mixture of water: acetonitrile (1: 1), 50 mg of bilastine (0.107 mmol). The solution obtained was stirred for 20 hours at room temperature until the solid crystallized. Subsequently, the solid was filtered and dried under vacuum. The X-ray diffraction analysis gave the diffractogram shown in Fig. 28.
 twenty
Example 8. Preparation of the crystalline form Eta of bilastine

Method 8A
The zeta form obtained in example 7 was introduced into a desiccator at 40 ° C and 75% relative humidity for one month. X-ray diffraction analysis gave the diffractogram shown in Fig. 30.

Method 8B
100 g of Bilastine, 587 mL of acetonitrile and 293 mL of water were loaded into a reactor. The mixture was heated at T = 55-60 ° C until complete dissolution of the solid. The solution was filtered to another reactor with mechanical stirring, previously heated to T = 50-55 ° C, and then washed with a mixture of 100 mL of water and 200 mL of acetonitrile at the same temperature and joined with the mixture previously filtered.
The filtered solution mixture was cooled to T = 40 ° C, ensuring that during this time the solid did not precipitate, and was seeded with 1.3 g of Bilastine Forma Eta. Then, it was maintained at T = 35-40 ° C for 40-45 min and, finally, it was cooled to a temperature of 5 ° C and maintained for about 2 hours at this temperature with stirring at all times. 5
The precipitated solid was centrifuged, washed with 200 mL of cold water, drained and dried under vacuum at T = 35 ° C until the water content was between 3.5-4.0% by weight (calculated by Karl Fischer method (KFT)). 85.60 g of Bilastine Forma Eta are obtained with a particle size of d10 = 4.5 µm; d50 = 15.8µm and d90 = 37.9 µm. 10
8C method
In a 500 mL Erlenmeyer equipped with magnetic stirring, 25 g of Bilastine Form Alpha and 250 mL of water were introduced. The suspension was kept under stirring between 20 and 25 ° C for 4 days.
The solid obtained was filtered and washed with 50 mL of water. It was dried in a vacuum oven at 15 T = 35 ° C until the water content was between 3.5-4.0% by weight (calculated by the Karl Fischer method (KFT)). 21.07 g of Bilastine Forma Eta were obtained.
Example 9. Stability study
 twenty
The stability study has been carried out with the crystalline forms of bilastine already known in the state of the art (crystalline forms 1, 2 and 3) and with the crystalline forms of bilastine described in the present invention. The crystalline forms used in the stability study have been prepared following the procedures described in the present invention. 25

The stability study involves storing each of the crystalline forms of bilastine separately at different conditions of time, temperature and relative humidity. The conditions of the stability study were the following:
 30
The results obtained from said stability study are described in Table 1:

Table 1
 Crystalline form  Terms
 1 month  2 months 3 months and 6 months
 25ºC / 60% RH  40 ° C / 75% RH 25 ° C / 60% RH 40 ° C / 75% RH 25 ° C / 60% RH 40 ° C / 75% RH
 one one one one one one one
 2 2 2 2 2 2 2
 3  3 + 1 3 + 1 3 + 1 1 + 3 - -
 Alpha Alpha Alpha Alpha Alpha Alpha Alpha
 Beta  Beta + 3 - - - - -
 Gamma A  2 + 3 + other crystalline forms 3 + 1 - - - -
 Gamma B  Gamma B + 3 1 + 3 + Alpha - -
 Delta  1 + Epsilon 1 1 1 - -
 Epsilon  1 + Eta 1 + Eta - - - -
 Zeta Zeta  Eta - - - -
 Eta Eta Eta Eta Eta Eta Eta
HR represents relative humidity

From the results of Table 1 it follows that the alpha and Eta crystalline forms of bilastine are stable under the conditions described, at least, up to 6 months. 5 Therefore, the alpha and Eta crystalline forms of bilastine are stable and suitable for the preparation of a pharmaceutical composition of bilastine.

Example 10. Formulations
 10
Composition

The quantitative tablet compositions comprising the crystalline alpha forms of bilastine of examples 1D-a and 1D-bo the crystalline form Eta of bilastine of example 8b of the present invention as well as the crystalline form 2 of 15 bilastine of comparative example 2B of the Present invention are described below.

The amounts of the ingredients expressed in milligrams per tablet are described in the following table 2.
   Table 2
 ingredients  Composition
 10A  10B 10C 10D
 Crystalline bilastine form  Alpha Ex. 1D-a Alpha ex. 1D-b Eta ex. 8B 2 ex.comp.2B
 Bilastine (*)  21.45 21.46 20.76 20.27
 Microcrystalline cellulose  96.68 96.67 97.37 97.86
 Magnesium stearate  1.25 1.25 1.25 1.25
 Sodium carboxymethyl starch  5.00 5.00 5.00 5.00
 Colloidal anhydrous silica  0.63 0.63 0.63 0.63
(*) Equivalent to 20 mg of anhydrous Bilastine; amount calculated per% water KF 5

Preparation Procedure

On the one hand, tablet 10A was obtained by wet granulation; while tablets 10B, 10C and 10D were obtained by direct compression. The procedures used in each case are described below.

Wet granulation
Microcrystalline cellulose, sodium carboxymethyl starch and bilastine were added to the mixer in the amounts specified in Table 2. The resulting mixture was homogenized in a turquoise mixer and kneaded with 135g of purified water on a planetary stirrer and dried for two hours at 50 ° C. The granulate obtained was mixed with the amount of anhydrous colloidal silica specified in Table 2 in a turbo mixer and then mixed with the amount of magnesium stearate specified in Table 2. Finally, tablets 20 were prepared by compression. of the mixture obtained in an eccentric compressing machine.

Direct compression

Microcrystalline cellulose, sodium carboxymethyl starch, bilastine and anhydrous colloidal silica were added to the mixer in the amounts specified in Table 2. The
The resulting mixture was homogenized in a turbo type mixer and then the amount of magnesium stearate specified in Table 2 was added and mixed in a turbo type mixer. Finally, the tablets were prepared by compression of the mixture obtained in an eccentric compressing machine.
 5
In all the tablets prepared in the present invention, the crystalline form of the bilastine used as the starting ingredient was maintained. The tablets obtained were conditioned in the form of Alu / Alu, PVC / Alu and PVC / PVDC (90 g / m2) / Alu blisters.
10

权利要求:
Claims (29)
[1]

1. Alpha crystalline form of bilastine characterized in that it has an X-ray diffractogram comprising characteristic peaks at 8.7; 11.6; 13.4; 13.8, 14.0 and 17.7 ± 0.2 degrees 2 theta measured with an X-ray diffractometer with Cu Kα 5 radiation (1.5418 Å).

[2]
2. Crystalline form of bilastine according to claim 1, wherein the X-ray diffractogram further comprises characteristic peaks at 18.6; 18.8; 20.1 and 21.1 ± 0.2 degrees 2 theta. 10

[3]
3. Crystalline form of bilastine according to any of claims 1-2, wherein the X-ray diffractogram further comprises peaks at 10.9; 12.2; 14.5; 15.0; 16.1; 17.4; 20.7; 21.4; 21.7; 21.9; 22.6; 23.3 and 23.5 ± 0.2 degrees 2 theta
 fifteen
[4]
4. Crystalline form of bilastine according to any of claims 1-3, characterized in that it has a DSC comprising a first broad endothermic phenomenon at 59 ° C with an associated heat of 89.0 J / g; a second broad endothermic phenomenon at 111 ° C with an associated heat of 15.9 J / g followed by an exothermic phenomenon at 117 ° C with an associated heat of 43.5 J / g; a third endothermic phenomenon 20 at 199 ° C with an associated heat of 100.4 J / g and a fourth endothermic phenomenon at 204 ° C with an associated heat of 9.7 J / g.

[5]
5. Crystalline form of bilastine according to any of claims 1-4, characterized by a thermogravimetry analysis comprising a weight loss of 5.9% from 30 ° C to 86 ° C.

[6]
Method for preparing the crystalline form of Bilastine Alpha defined in any one of claims 1-5, characterized in that it comprises a) obtaining bilastine from a dispersion of bilastine form 1 in water. 30

[7]
7. Preparation process according to claim 6, characterized in that the amount of water in step a) is from 6 mL / g to 100 mL / g of starting bilastine.
[8]
8. Preparation process according to any of claims 6-7, characterized in that step a) of obtaining bilastine comprises the following steps:
a ') heating a mixture of bilastine in water at a temperature of from 40 ° C to 95 ° C;
a '') cooling the dispersion obtained in step a ') to room temperature; Y
a '' ') stir the dispersion obtained in step a' ') for the period of time necessary for the transformation to occur.
 10
[9]
9. Preparation process according to any of claims 6-7, characterized in that step a) of obtaining bilastine comprises the following steps:
      e ') suspend bilastine in water at room temperature; and 15
      e '') stir the suspension obtained in step e ') during the period of time that
      It is necessary for the transformation to occur.

[10]
10. Preparation process according to any of claims 8-9, characterized in that the stirring of stage a '' ') or alternatively of stage e' ') is carried out for a period of time from 24 hours to 75 hours

[11]
11. Preparation process according to any of claims 6-10, characterized in that the obtention of bilastine further comprises the following 25 steps:
b) Isolate the crystalline bilastine obtained in stage a ’’ ’) or alternatively in stage e’ ’); Y
c) Separate the water from the bilastine obtained in step b). 30

[12]
12. Method of preparing the crystalline form of bilastine alpha defined in any of claims 1-5, characterized in that it is a crystallization process comprising the following steps:
a1) dissolve bilastine in a mixture of water and ethanol at a temperature from 75 ° C to 100 ° C;
a2) cooling the solution obtained in step a1) to a temperature from 50 ° C to 75 ° C;
a3) sow the solution obtained in step a2) with the alpha crystalline form and cool the resulting solution to a temperature of 0 ° C to 25 ° C for the period of time necessary for crystallization to occur; Y
a3 ’) drying the crystalline form obtained in step a3) under reduced pressure at a temperature from 25C to 40 ° C until the water content 10 is comprised from 6% to 8% by weight calculated by the Karl Fischer method.

[13]
13. Method of preparing the crystalline form of Bilastine Alpha defined in any of claims 1-5, characterized in that it is a crystallization process comprising the following steps:
a4) dissolve bilastine in a mixture of water, ice and a base at a temperature of 15ºC to 35ºC;
a5) add to the solution obtained in step a4) an aqueous acidic solution 20 to a pH from 6 to 8 for crystallization to occur; Y
a6) drying the crystalline form obtained in step a5) under reduced pressure at a temperature of from 25 ° C to 40 ° C until the water content is comprised from 6% to 8% by weight calculated by the Karl Fischer method. 25

[14]
14. Eta crystalline form of bilastine characterized in that it has an X-ray diffractogram comprising characteristic peaks at 8.4; 9.6; 12.2; 13, 2; 15.1; and 19.2 ± 0.2 degrees 2 theta measured with an X-ray diffractometer with Cu Kα radiation (1.5418 Å). 30

[15]
15. Crystalline form of bilastine according to claim 14, wherein the X-ray diffractogram further comprises characteristic peaks at 19.7; 20.3; 21.5; and 23.4 ± 0.2 degrees 2 theta.
 35
[16]
16. Crystalline form of bilastine according to any of claims 14-15, wherein the X-ray diffractogram further comprises peaks at 14.0; 16.8; 17.5; 18.2 and 25.5 ± 0.2 degrees 2 theta.

[17]
17. Crystalline form of bilastine according to any of claims 14-16, characterized in that it has a DSC comprising a first broad endothermic phenomenon with a peak at 137 ° C with an associated heat of 35.4 J / g followed by a second endothermic phenomenon at 198 ° C with an associated heat of 13.4 J / g overlapped with an exothermic phenomenon with a peak at 200 ° C and with an associated heat of 14.0 J / g and followed by a third endothermic phenomenon at 204 ° C with an associated heat of 101, 3 10 J / g.

[18]
18. Crystalline form of bilastine according to any of claims 14-17, characterized by a thermogravimetry analysis comprising a weight loss of 4.0% from 30 ° C to 120 ° C. fifteen

[19]
19. Method of preparing the crystalline form Eta of bilastine defined in any of claims 14-18, characterized in that it comprises dispersing in water the crystalline form Alfa or a mixture of crystalline form Alfa and Eta for a period of time necessary for it to occur the transformation to the crystalline form 20 Eta of bilastine.

[20]
20. Method for preparing the crystalline form Eta of bilastine defined in any of claims 14-18, characterized in that it comprises the following steps:
i) Dissolve bilastine in a mixture of water and acetonitrile at a temperature of 40ºC to 70ºC;
ii) cooling the solution obtained in step i) to a temperature of from 25 ° C to 50 ° C; 30
iii) sow the solution obtained in step ii) with the crystalline form Eta and cool the resulting solution to a temperature of 0 ° C to 30 ° C for the period of time necessary for crystallization to occur; Y
iv) drying the crystalline form obtained in step iii) under reduced pressure at a temperature from 25 ° C to 40 ° C until the water content 35
is comprised from 3.5% to 4% by weight calculated by the Karl Fischer method.

[21]
21. Preparation process of the crystalline form Eta of bilastine defined in claim 20, characterized in that in step iv) it is carried out under reduced pressure at a temperature of from 30 ° C to 35 ° C.

[22]
22. Method of preparing the crystalline form Eta of bilastine defined in any of claims 14-18, characterized in that it comprises maintaining the crystalline form Zeta at a temperature of from 20 ° C to 50 ° C for a period of time necessary for the transformation to occur to the crystalline form Eta of bilastine.

[23]
23. Method of preparing the crystalline form Eta of bilastine defined in claim 22, characterized in that it comprises maintaining the crystalline form Zeta at a temperature comprised from 25 ° C to 40 ° C.

[24]
24. Method for preparing the crystalline form Eta of bilastine defined in any one of claims 22-23, characterized in that it comprises maintaining the crystalline form Zeta at a temperature of from 30 ° C to 35 ° C until 20 that the water content is comprised from 3, 5% and 4% by weight calculated by the Karl Fischer method.

[25]
25. Method for preparing the crystalline form Eta of bilastine defined in any of claims 14-18, characterized in that it comprises maintaining the Zeta crystalline form at a temperature of from 35 ° C to 45 ° C and a relative humidity of from 65% to 80% for a period of time necessary for the transformation to the crystalline form Eta of bilastine.

[26]
26. Method of preparing the crystalline form Eta of bilastine defined in claim 25, characterized in that it comprises maintaining the crystalline form Zeta for a period of time longer than 2 weeks.

[27]
27. Pharmaceutical composition comprising a therapeutically effective amount of the alpha crystalline form of bilastine defined in any of claims 1-35
5, or alternatively of the crystalline form of bilastine Eta defined in any of claims 14-18 together with pharmaceutically acceptable excipients or carriers.

[28]
28. Use of the crystalline form Alpha of bilastine according to any of claims 5 1-5 or alternatively of the crystalline form Eta of bilastine defined in any of claims 14-18, for the preparation of a medicament for the treatment of reactions Allergic and pathological processes mediated by histamine.
 10
[29]
29. Use according to claim 28, wherein the treatment of allergic reactions and pathological processes mediated by histamine is selected from the group consisting of the symptomatic treatment of seasonal allergic rhinoconjunctivitis, the symptomatic treatment of perennial allergic rhinoconjunctivitis and the treatment of urticaria.

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