ES2245227B1 - CRYSTALLINE FORMS OF MIZOLASTINE, PROCEDURES FOR OBTAINING AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. - Google Patents

Abstract

Crystalline forms of mizolastine, procedures for obtaining them and pharmaceutical compositions containing them. A crystalline form of mizolastin substantially free of water and solvent, called Form A, and another crystalline form of mizolastin substantially free of solvent, called Form B, characterized by infrared spectroscopy, differential scanning calorimetry and X-ray powder diffraction are described. Said crystalline forms can be obtained by recrystallization of mizolastine in an organic solvent in the presence or absence of water. Pharmaceutical compositions containing such crystalline forms are useful for the treatment of allergic conditions.

Description

Crystalline forms of mizolastine, procedures for obtaining and pharmaceutical compositions that They contain them.

Field of the Invention

The invention relates to crystalline forms of mizolastine, to procedures for obtaining it and to compositions Pharmaceuticals that contain them.

Background of the invention

Mizolastine (D.C.I.) [2 - ({1- [1- (4-Fluorobenzyl) -1H-benzimidazol-2-yl] -piperidin-4-yl} -methylamino) -4 (1H) pyrimidone] it is a benzimidazole derivative that has properties selective H receptor antagonists for histamine. It was first described in European patent EP 0 217 700 B1.

Several European patents describe several synthesis methods of mizolastine, and other analogous compounds derivatives of 1- (1H-benzimidazol-2-yl) -4- (2-aminopyrimidin) piperidine, as well as the use of that compound in the symptomatic treatment of allergies, both at the respiratory level, as cutaneous, ocular, etc., by pharmaceutical forms of oral or parenteral administration, where one of its main advantages lies in its prolonged action against others drugs

Surprisingly, it was not found in the literature (also in European patent EP 0 217 700 B1), data about the physical properties of the product. In fact, in the patent European EP 0 217 700 B1 only states that mizolastine can be recrystallize from ethanol and that said compound has a point of melting of 217 ° C.

As is known, the different ways crystallines that a compound can present lead to a variation in its physical-chemical parameters, such such as stability, dissolution rate, point of fusion, etc. This variation in the properties of the compound, is translates into a different bioavailability of it, especially when the active substance is administered in solid form.

From the pharmaceutical point of view, it is important to control the obtaining of the product in the form desired crystalline, to solve problems of lack of reproducibility in the handling of the product or its bioavailability

During the course of investigations performed on obtaining mizolastine by more appropriate routes of synthesis (Spanish patent application P200202251), the inventors have observed the appearance of different forms crystalline depending on the crystallization conditions of the product.

These crystalline forms differ in their infrared (IR) spectra, in their endotherms by calorimetry scanning differential (DSC), at melting points (PF) and in their X-ray diffractograms (DRX).

Therefore, in one aspect the invention is relates to new crystalline forms of mizolastine, called Form A and Form B in this description, identified and characterized by IR, DSC, PF and DRX. The present invention analyzes, furthermore, the relative stability of said crystalline forms and their different properties

In another aspect, the invention relates to procedures for preparation, unequivocally and reproducible, of said crystalline forms of mizolastine. In a particular embodiment, a procedure for the Preparation of Form A. In another particular embodiment, provides a procedure for the preparation of Form B.

In another aspect, the invention relates to a pharmaceutical composition comprising a crystalline form of mizolastine selected from Form A, Form B, and their mixtures, together with a pharmaceutically acceptable excipient.

In another aspect, the invention relates to the use of a crystalline form of mizolastin selected from Form A, Form B, and mixtures thereof, in the preparation of a appropriate medication for the symptomatic treatment of conditions allergic, such as allergic rhinitis, allergic urticaria, the  pruritus, etc.

In another aspect, the invention relates to a method for the symptomatic treatment of a subject, such as a human or animal, with allergic conditions, in need of treatment, which comprises applying to said subject an amount therapeutically effective of a crystalline form of mizolastine selected from Form A, Form B and their mixtures.

Brief description of the figures

Figure 1 is a graph showing the infrared (IR) spectrum of the crystalline form of mizolastine called Form A made in bromide tablet potassium, in an infrared spectrophotometer with transformed Fourier (FT-IR) Perkin-Elmer 1600. On the ordinate axis the transmittance is represented and on the abscissa axis the number of waves (cm -1).

Figure 2 is a graph showing the differential scanning calorimetry endothermia (DSC) of the crystalline form of mizolastin called Form A. On the axis of sorted represents the energy absorbed or transmitted by unit of time (mW) and on the abscissa axis the temperature (ºC) and the time (minutes).

Figure 3 is a graph showing the X-ray powder diffraction spectrum (DRX) of the form mizolastine crystal called Form A, obtained at λ = 1,5406 angstrom (\ ring {A}), using a radiation source CuK? 1, 40 kV and 30 mA (equipment Debye-Scherrer INEL CPS-120). At ordinate axis pulses are represented and on the axis of abscissa the angle 2?

Figure 4 is a graph showing the infrared (IR) spectrum of the crystalline form of mizolastine called Form B made in bromide tablet potassium in an FT-IR spectrophotometer Perkin-Elmer 1600. On the ordinate axis, represents the transmittance and on the abscissa axis the number of waves (cm -1).

Figure 5 is a graph showing the differential scanning calorimetry endothermia (DSC) of the crystalline form of mizolastin called Form B. On the axis of sorted represents the energy absorbed or transmitted by unit of time (mW) and on the abscissa axis the temperature (ºC) and the time (minutes).

Figure 6 is a graph showing the X-ray powder diffraction spectrum (DRX) of the form mizolastine crystal called Form B, obtained at λ = 1,5406 angstrom, using a CuKα1 radiation source, 40 kV and 30 mA (Debye-Scherrer INEL equipment CPS-120). The ordered axis represents the impulses and on the abscissa axis the angle 2?.

Figure 7 is a graph showing the Endothermias by differential scanning calorimetry (DSC) of a mixture comprising the crystalline forms of mizolastine called Forms A and B, being able to observe the existence of 2 DSC bands when mixtures of such forms are obtained crystalline The energy axis is represented on the ordinate axis absorbed or transmitted per unit of time (mW) and on the axis of you abscissa the temperature (ºC) and the time (minutes).

Detailed description of the invention

In a first aspect the invention relates with crystalline forms of mizolastine, called Form A and Form B.

Form A has been characterized by its spectrum of infrared absorption (IR), its endothermia by calorimetry scanning differential (DSC), its melting point (PF) and its X-ray diffractogram (DRX).

Form A exhibits an infrared spectrum (IR) in potassium bromide tablets substantially similar to shown in Figure 1, which has significant bands at approximately 3500, 2900, 1646, 1569, 1508, 1458, 1399, 1371, 1313, 1281, 1242, 1225, 1159, 1142, 1029, 970, 825, 804, 743, 545, 505 cm -1.

Endothermic registration by calorimetry Scan Differential (DSC) of Form A has a maximum of Approximately 225 ° C, which corresponds to the endothermic phenomenon of Fusion of Form A (see Figure 2). The endothermic registry by DSC it was performed in a closed vessel, at a temperature included between 25ºC and 320ºC, with a heating rate of 10ºC / min, in a Mettler Toledo Star System team.

Form A presents a melting point (PF) corresponding to 223-224 ° C.

Form A presents an X-ray diffractogram (DRX) substantially similar to that shown in Figure 3, with spikes characteristic at 5.17, 4.95, 4.32, 4.08, 3.82, and 3.44 degrees 2 theta (2?), using a CuK? 1 radiation source, 40 kV and 30 mA (Debye-Scherrer INEL equipment CPS-120).

Form A is a crystalline form substantially free of water and solvent, as it has been proven by conventional techniques, such as gas chromatography and titration against the reagent of Karl-Fischer (KF). In the sense used in this description, the expression "substantially free of water and solvent "means that it has a lower water content than 0.3% by weight and a residual solvent content less than 0.5% by weight.

Form B has been characterized by its spectrum of infrared absorption (IR), its endothermia by calorimetry scanning differential (DSC) and its X-ray diffractogram (DRX)

Form B exhibits an infrared spectrum (IR) in potassium bromide tablets substantially similar to shown in Figure 4, which has significant bands at approximately 3500, 2900, 1653, 1560, 1521, 1508, 1458, 1405, 1371, 1312, 1281, 1253, 1214, 1143, 1027, 971, 824, 804, 743, 546, 516 cm -1.

Endothermic registration by calorimetry Scan Differential (DSC) of Form A has a maximum of 217 ° C approximately, which corresponds to the endothermic phenomenon of Fusion of Form B (see Figure 5). The endothermic registry by DSC it was performed in a closed vessel, at a temperature included between 25ºC and 320ºC, with a heating rate of 10ºC / min, in a Mettler Toledo Star System team.

Form B presents a melting point corresponding to 214-215 ° C.

Form B presents an X-ray diffractogram (DRX) substantially similar to that shown in Figure 6, with spikes characteristic at 10.66, 7.80, 6.98, 6.30, 5.48, 4.81, 4.48, 4.32, 3.84, 3.74 degrees 2 theta (2 the), using a source of CuK? 1 radiation, 40 kV and 30 mA (equipment Debye-Scherrer INEL CPS-120).

Form B is a crystalline form substantially free of solvent, containing between 1.1% and 1.4% by weight of water, as has been proven by techniques conventional, such as gas chromatography and titration against Karl-Fischer reagent. In the meaning used in this description, the expression "substantially solvent free" means that it has a residual solvent content less than 0.5% by weight.

In view of previously analytical data mentioned, it can be affirmed that Form A and Form B are two different crystalline forms of mizolastine that can be easily distinguished by IR, DSC, RX and PF.

Form B, maintained in a forced air stove at 60 ° C until constant weight (24-36 hours) loses partially water until reaching 0.6% by weight of water. This "partially anhydrated" product, left at temperature ambient to air, over time, recovers lost water until having between 1.1% and 1.4% by weight of water, typically between  1.2% and 1.3% by weight of water. Both this product and the product partially anhydrified, have the same bands of infrared and the same melting point, so the presence or Absence of water does not affect the crystalline form itself.

Unlike Form B, Form A does not it has a tendency to absorb water, that is, it is not hygroscopic, as evidenced in a simple experiment in which crystals corresponding to Form A are resuspended in water with Stirring, heat to reflux temperature for 6 hours, allowed to cool, separated from water by filtration and dried in a forced air oven at 60 ° C until constant weight, giving a KF less than 0.1%. The product obtained, still has the same properties of Form A and does not absorb water with the weather.

Form B crystals dissolve more easily in ethanol than those in Form A as it gets from shown in Example 16 [30 ° C / 24 hours (Example 16A) or 50 ° C / 24 hours (Example 16B)].

IR studies, carried out in a pill of potassium bromide, have provided results that allow differentiate both crystalline forms of mizolastine. In fact, the infrared (IR) spectroscopy is a very useful tool for differentiate between both Forms A and B, even when there are mixtures of the same. X-ray powder diffraction characterization of Forms A and B is also significantly different, which highlights the existence of two crystalline forms different. As is known, X-ray studies constitute the best tool to differentiate between two crystalline forms and determine the existence of mixtures of crystalline forms, since that each crystalline form has different diffractions and characteristics and therefore can be unequivocally identified each of said crystalline forms and determine the existence of mixtures thereof. In addition, this technique is quantitative and allows quantifying the amount of each of the forms crystallines present in a mixture of both crystalline forms. Both Forms A and B have been characterized using techniques conventional so that a person skilled in the art can identify without problems each of them or a mixture of same.

In another aspect, the invention relates to procedures for obtaining, unequivocally and fully reproducible, of Forms A and B of mizolastine provided by this invention. Numerous trials conducted by the inventors have shown that, depending on the crystallization conditions, each of the Forms A or B of mizolastine independently and reproducible.

In general, Forms A and B of mizolastine they can be obtained by crystallization in an organic solvent determined in the absence or in the presence of water from mizolastine Surprisingly, the parameters that govern the obtaining a crystalline or other form, in pure form or mixture and reproducibly, there are several: the organic solvent used, the concentration of water in the medium, and planting or not in crystallization Also, surprisingly, it has been found that Form A is obtained under crystallization conditions with a pure organic solvent, or with a certain water content, while Form B is obtained, in general with others pure organic solvents other than the above or with the same organic solvents as those used to obtain the Form A but with higher concentrations of water in the medium. The Examples 1 to 18 confirm that the crystallization conditions they are very specific and that not all organic solvents or any amount of water leads to pure A or B forms. By both, obtaining a crystalline or other form, or a mixture of both, and the reproducibility of the crystallization procedure simultaneously depends on several critical parameters and particular in each case.

In general, the percentages indicated in This description refers to percentage by weight / weight (w / w) except otherwise indicated.

Form A can be obtained by techniques conventional recrystallization of mizolastin in different organic solvents, for example, ethanol, toluene, xylene, ethyl acetate, acetonitrile, dimethylformamide or butan-2-ol, in the absence of water or either in the presence of water, in an amount equal to or less than 8% in water weight The starting mizolastine can be any Mizolastine, both non-crystalline and crystalline, for example, in Form A, Form B, mixtures of Form A and B, etc. Do not However, in general, in the Examples, the starting mizolastin used is a purified mizolastine by recrystallization in ethanol (Form A) unless otherwise indicated.

More specifically, in one embodiment In particular, the invention provides a method for obtaining Form A of mizolastine by recrystallization in a organic solvent comprising:

to)

dissolve mizolastin in a solvent organic selected from ethanol, toluene, xylene, acetate ethyl, acetonitrile, dimethylformamide and butan-2-ol; Y

b)

bring the obtained mixture to a temperature between 2ºC and 40ºC, and filter the suspension resulting.

In general, the solution of mizolastin is favors by heating the mixture formed by mizolastine and the solvent The heating temperature is chosen so that favor dissolution without adversely affecting the product. In a particular embodiment, the mixture Mizolastin-solvent is heated to temperature of solvent reflux. Additionally, sometimes, it can be it is necessary to evaporate part of the organic solvent used with the in order to achieve supersaturation of the mixture.

In different particular embodiments, the Mizolastine is dissolved in ethanol, toluene, xylene, acetate ethyl or butan-2-ol, respectively, at reflux (Examples 1, 3, 4, 5 and 10). In another embodiment In particular, mizolastin is dissolved in acetonitrile at reflux and excess solvent is removed by distillation until it reaches supersaturation of the mixture (Example 6). In another embodiment In particular, mizolastine dissolves in dimethylformamide at 100 ° C until complete dissolution of the mizolastine (Example 7).

Preferably, said organic solvent is ethanol, which can be totally anhydrous or can contain water up to a weight ratio of ethanol / water of 92/8, whereby crystalline form A is obtained exclusively.
(Example 15).

Mizolastin Form B can be obtained at starting from mizolastine using conventional techniques of recrystallization from an organic solvent, for example, propan-2-ol, in the absence of water, or either in an organic solvent such as ethanol, acetonitrile, dimethylformamide or propan-2-ol, in presence of a certain amount of water.

More specifically, the invention provides a procedure for obtaining Form B, procedure B.I, comprising:

to)

mix mizolastine with propan-2-ol; Y

b)

bring the obtained mixture to a temperature between 2ºC and 40ºC, and filter the suspension resulting.

In general, the dissolution of the mizolastine is favored by heating the mixture formed by the mizolastine and the propan-2-ol at a temperature such that it favors the dissolution of the mizolastine without adversely affecting the product. In a particular embodiment, the mizolastin-propan-2-ol mixture is heated to the reflux temperature of the solvent.
(Example 9).

Alternatively, Mizolastin Form B can be obtained from mizolastine by techniques conventional recrystallization in different solvents organic, for example, ethanol, acetonitrile, dimethylformamide or propan-2-ol, in the presence of a water quantity greater than 8% by weight.

Therefore, in another particular embodiment, the invention provides a method for obtaining the Form B of mizolastine by recrystallization from a solvent organic, in the presence of water, called procedure B.II, which understands:

to)

mix mizolastine with a solvent organic selected from ethanol, acetonitrile, dimethylformamide and propan-2-ol;

b)

add water to the mixture formed in step a), in an amount sufficient to dissolve completely mizolastine;

C)

add water to the solution obtained in stage b), in an amount sufficient to reach the supersaturation; Y

d)

bring the mixture obtained in the stage c) up to a temperature between 2ºC and 40ºC, and filter the resulting suspension.

In general, the dissolution of mizolastin in the organic solvent is favored by heating the mixture formed by mizolastine and solvent at a temperature that favors the dissolution of mizolastine without adversely affecting the product. In a particular embodiment, the mixture Mizolastin-solvent is heated to temperature of solvent reflux.

To the mixture of mizolastine and organic solvent resulting water is added in an amount sufficient to completely dissolve the undissolved mizolastin in said mixture; that is, water is added until the complete dissolution of the starting mizolastin in the solvent organic. The amount of water to be added will depend on each case. particular of the nature of the solvent used, of the amount of mizolastine to dissolve and the temperature of the mixture. However, the amount of water to be added may be easily determined in each particular case by an expert in the matter. Typically the amount of water to add to the mixture Mizolastine and water is greater than 8% by weight.

At dissolution of mizolastin in the solvent organic and water is added water in a sufficient amount as to achieve supersaturation. Advantageously, this new water addition takes place keeping the mixture hot, typically at the reflux temperature of the solvent system, with agitation. The amount of water to be added will depend on each case. particular of the nature of the solvent used, of the amount of mizolastine to dissolve and the temperature of the mixture. However, the amount of water to be added may be easily determined in each particular case by an expert in the matter. Typically the amount of water to add to the mixture Mizolastine and water is greater than 8% by weight.

In different particular embodiments, the Organic solvent used is selected from ethanol, acetonitrile, dimethylformamide and propan-2-ol (Examples 2, 11, 12 and 14). In another particular embodiment, the solvent is ethanol and the amount of total water added present at the end of stage c) it is such that the weight ratio of ethanol / water is comprised between 50/50 and 88/12. Various trials conducted by researchers have revealed that when the content in water present in a solvent system composed of ethanol and water is between 12% and 50% by weight, Form B is obtained, while when the water content present in a system solvent composed of ethanol and water is between 0% and 8% by weight, Form A is obtained. However, when the content in water present in a solvent system composed of ethanol and Water is greater than 8% and less than 12%, Form A or B are obtained well pure or mixtures of Form A and Form B. In particular, tests carried out under the same experimental conditions and with an ethanol / water weight ratio of 90/10 yielded Form A free of Form B, Form B free of Form A, or mixtures of Both Forms A and B in various proportions.

Alternatively, Mizolastin Form B can be obtained as a majority polymorph of a mixture that comprises Form A and Form B, using conventional techniques recrystallization in different organic solvents, by example, ethanol, toluene, xylene, acetonitrile, dimethylformamide, butan-2-ol or propan-2-ol, and crystal sowing of Form B.

Therefore, more specifically, the invention provides a procedure for obtaining the majority of the Form B of mizolastine, called procedure B.III, which understands:

to)

mix mizolastine with a solvent organic selected from ethanol, toluene, xylene, acetonitrile, dimethylformamide, butan-2-ol and propan-2-ol; Y

b)

bring the mixture obtained in the stage a) up to a temperature between 2ºC and 40ºC, in the presence of Form B crystals, and filter the suspension resulting.

As in the procedures previously described, the mixture of mizolastine and organic solvent is performed by heating the mixture to a temperature that favors the dissolution of mizolastine without adversely affecting the product. In a particular embodiment, the mixture Mizolastin-solvent is heated to temperature of solvent reflux.

The amount of crystals of Form B of Mizolastine to be added as sowing may vary within a wide range. interval. However, in a particular embodiment, planting of Form B crystals comprises adding an equivalent amount, at least 5% by weight of the mizolastine to be recrystallized.

In a particular embodiment the solvent organic used is ethanol and the weight ratio of Forms crystalline A / B in the mixture obtained is 1/60 respectively (Example 17).

The crystals obtained in each case, after be filtered, if desired, dried to constant weight, by for example, in a forced air oven at 60ºC to constant weight, and are identified by the techniques discussed above IR, DSC, RX and PF. The contents in residual solvents and water collected in the crystalline structure are analyzed by chromatography of gases and titration against the reagent of Karl-Fischer respectively. The solids identified as Form A and B constitute well formed crystals in the form of prisms. Such pure and well crystalline forms defined respectively give rise to a single band per DSC, without appearance of mixtures of them (Figures 2 and 5). In cases in that mixtures of both crystalline forms were obtained (Forms A and B) two bands appeared in DSC (Figure 7).

Mizolastine is an antiallergic, long-lasting antihistamine that acts as an antagonist of H1 histamine receptors, preferably at the level peripheral, preventing the released histamine from acting on the effector cells, so it is useful for treatment symptomatic of allergic conditions, for example, allergic rhinitis, pruritus or hives Forms A and B of mizolastine can be used in the same therapeutic indications as the mizolastine, for example, in the symptomatic treatment of allergic conditions

Thus, in another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of mizolastine, selected from Form A, Form B, and mixtures thereof, together with a pharmaceutically acceptable carrier or excipient. In general, the pharmaceutical composition of the present invention will be adapted for oral, parenteral, topical, etc. administration. A review of the different pharmaceutical forms of drug administration and their preparation can be found in the book "Galenica Pharmacy Treaty", by C. Faulí i Trillo, 1st Edition, 1993, Luzán 5, SA de Edicio-
nes.

Also, in another aspect, the invention relates to the use of a crystalline form of mizolastine, selected from Form A, Form B and mixtures thereof, in the preparation of a medicament suitable for the symptomatic treatment of allergic conditions, such such as allergic rhinitis, allergic urticaria, pruritus,
etc.

In another aspect, the invention relates to a method for the symptomatic treatment of a subject, such as a human or animal, with allergic conditions, in need of treatment, which comprises applying to said subject an amount therapeutically effective of a crystalline form of mizolastine selected from Form A, Form B and their mixtures.

The following examples illustrate the invention and should not be considered as limiting thereof. Examples 1, 3, 4, 5, 6, 7, 10 and 15 describe the obtaining of Form A, while Examples 2, 9, 11, 12 and 14 describe the obtaining of Form B of mizolastine. Examples 8, 13, 17 and 18 describe obtaining mixtures of Forms A and B. Example 16 illustrates the solubility of said Forms A and B in ethanol under different conditions.
nes.

Example 1 Preparation of crystalline form A

1 g of mizolastin was dissolved in 24 mL of ethanol at reflux. The solution was cooled slowly to a approximate temperature of 5ºC. The mixture was filtered and the solid obtained was dried in a forced air oven at 60 ° C to weight constant. 0.8 g of mizolastine were obtained in the crystalline form TO.

IR (cm -1): 3500, 2900, 1646, 1569, 1508, 1458, 1399, 1371, 1313, 1281, 1242, 1225, 1159, 1142, 1029, 970, 825, 804, 743, 545, 505 (Figure 1).

Melting Point (PF): 223-224 ° C.

DSC (closed cup, between 25ºC and 320ºC, 10ºC / min heating rate): maximum at approximately 225 ° C (Figure 2).

DRX: characteristic peaks at 5.17, 4.95, 4.32, 4.08, 3.82, and 3.44 degrees 2? (Figure 3).

KF: 0.08%.

Example 2 Preparation of crystalline form B

On a 5 g suspension of mizolastine from crystalline form A in 30 mL of ethanol at reflux were added slowly 6 mL of water. It was stirred at reflux for 30 minutes and 23 mL more water and slowly added to this solution then a slight turbidity was observed. The mixture cooled slowly to an approximate temperature of 5 ° C, it was filtered and the solid obtained was dried in a forced air oven at 60 ° C until constant weight 4.53 g of mizolastin were obtained in the form crystalline B.

IR (cm -1): 3500, 2900, 1653, 1560, 1521, 1508, 1458, 1405, 1371, 1312, 1281, 1253, 1214, 1143, 1027, 971, 824, 804, 743, 546, 516 (Figure 4).

MP: 214-215 ° C.

DSC (closed cup, between 25ºC and 320ºC, 10ºC / min heating rate): maximum at approximately 217 ° C (Figure 5).

DRX: characteristic to characteristic peaks to 10.66, 7.80, 6.98, 6.30, 5.48, 4.81, 4.48, 4.32, 3.84, 3.74 degrees 2? (Figure 6).

KF: 1.4%.

Example 3 Crystallization of mizolastine in toluene

1 g of mizolastin was dissolved as crystalline A in 19 mL of toluene at reflux. The solution cooled slowly to an approximate temperature of 5 ° C. The mixture is filtered and the solid obtained was dried in a forced air oven at 60ºC to constant weight. 0.87 g of mizolastin was obtained in the  crystalline form A, confirmed by PF, IR and DSC. KF: 0.07%

Example 4 Crystallization of mizolastine in xylene

1.5 g of mizolastin were dissolved as crystalline A in 13 mL of xylene at reflux. The solution cooled slowly to an approximate temperature of 5 ° C. The mixture is filtered and the solid obtained was dried in a forced air oven at 60ºC to constant weight. 1.34 g of mizolastin were obtained in the  crystalline form A, confirmed by PF, IR and DSC. KF: 0.1%.

Example 5 Crystallization of mizolastine in ethyl acetate

1 g of mizolastin was dissolved as crystalline A in 125 mL of ethyl acetate at reflux. They distilled 78 mL of solvent to saturation, and the solution was cooled slowly to an approximate temperature of 5 ° C. The mixture is filtered and the solid obtained was dried in a forced air oven at 60ºC to constant weight. 0.9 g of mizolastine were obtained in the crystalline form A, confirmed by PF, IR and DSC. KF: 0.6%.

Example 6 Crystallization of mizolastine in acetonitrile

1 g of mizolastin was dissolved as crystalline A in 180 mL of acetonitrile at reflux. 106 were distilled mL of solvent to saturation, and the solution was cooled slowly to an approximate temperature of 5 ° C. The mixture is filtered and the solid obtained was dried in a forced air oven at 60ºC to constant weight. 0.85 g of mizolastin was obtained in the crystalline form A, confirmed by PF, IR and DSC. KF: 0.1%.

Example 7 Crystallization of mizolastine in dimethylformamide

1 g of mizolastin was dissolved as crystalline A in 2 mL of dimethylformamide at 100 ° C. The solution is cooled slowly to an approximate temperature of 5 ° C. The mixture was filtered and the solid obtained was dried in an air oven forced at 60 ° C to constant weight. 0.62 g of mizolastine in crystalline form A, confirmed by PF, IR and DSC KF: 0.05%.

Example 8 Crystallization of mizolastine in tetrahydrofuran

1 g of mizolastin was dissolved as crystalline A in 39 mL of tetrahydrofuran at reflux. Dissolution it cooled slowly to an approximate temperature of 5 ° C. The mixture was filtered and the solid obtained was dried in an air oven forced at 60 ° C to constant weight. 0.77 g of mizolastine as a mixture of crystalline forms A and B, in a Weight ratio Form A / Form B of 1 / 2.7, confirmed by PF, IR and DSC. KF: 0.3%.

Example 9 Crystallization of mizolastin in propan-2-ol

1 g of mizolastin was dissolved as crystalline A in 60 mL of propan-2-ol  at reflux. The solution was cooled slowly to a temperature. Approximately 5ºC. The mixture was filtered and the solid obtained dried. in a forced air oven at 60ºC to constant weight. Be they obtained 0.82 g of mizolastine in crystalline form B, confirmed by PF, IR and DSC. KF: 0.9%.

Example 10 Crystallization of mizolastin in butan-2-ol

1 g of mizolastin was dissolved as crystalline A in 10 mL of butan-2-ol at reflux. The solution was cooled slowly to a temperature. Approximately 5ºC. The mixture was filtered and the solid obtained dried. in a forced air oven at 60ºC to constant weight. Be they obtained 0.85 g of mizolastine in crystalline form A, confirmed by PF, IR and DSC. KF: 0.1%.

Example 11 Crystallization of mizolastine in acetonitrile / water

On a suspension of 1 g of crystalline A mizolastine in 10 mL of acetonitrile at reflux, 2 mL of water was slowly added. It was stirred at reflux for 30 minutes and 11 mL more water was added slowly over this solution and then a slight turbidity was observed. The mixture was cooled slowly to an approximate temperature of 5 ° C, filtered and the solid obtained was dried in a forced air oven at 60 ° C to constant weight. 0.74 g of mizolastin were obtained in crystalline form B, confirmed by PF, IR and DSC. KF:
1.2%

Example 12 Crystallization of mizolastine in dimethylformamide / water

On a suspension of 1 g of mizolastine from crystalline form A in 4 mL of dimethylformamide at reflux is slowly added 2.8 mL of water. The mixture cooled slowly to an approximate temperature of 5 ° C, it was filtered and the solid obtained was dried in a forced air oven at 60 ° C until constant weight 0.85 g of mizolastin was obtained in the form crystalline B, confirmed by PF, IR and DSC. KF: 0.73%.

Example 13 Crystallization of mizolastine in tetrahydrofuran / water

On a suspension of 1 g of mizolastine from crystalline form A in 10 mL of tetrahydrofuran at reflux is slowly added 3 mL of water. It was stirred at reflux for 30 minutes and 10 mL more slowly added to this solution of water and then a slight turbidity was observed. The mixture is cooled slowly to an approximate temperature of 5 ° C, it filtered and the solid obtained was dried in a forced air oven at 60ºC to constant weight. 0.73 g of mizolastin was obtained as a mixture of crystalline forms A and B, in a weight ratio Form A / Form B of 1 / 4.8, confirmed by PF, IR and DSC. KF: 0.5%

Example 14 Crystallization of mizolastin in propan-2-ol / water

On a suspension of 1 g of crystalline A mizolastine in 10 mL of propan-2-ol at reflux, 3 mL of water was slowly added. It was stirred at reflux for 30 minutes and over this solution 15 mL more water was slowly added and then a slight turbidity was observed. The mixture was cooled slowly to an approximate temperature of 5 ° C, filtered and the solid obtained was dried in a forced air oven at 60 ° C to constant weight. 0.79 g of mizolastin were obtained in crystalline form B, confirmed by PF, IR and DSC. KF:
1.4%

Example 15 Crystallization of mizolastine in ethanol / water (92/8)

1 g of mizolastin was dissolved as crystalline A in 10 mL of an ethanol / water solution (92/8) at Reflux. The solution was cooled slowly to a temperature. Approximately 5 ° C, it was filtered and the solid obtained was dried in a forced air stove at 60ºC to constant weight. They were obtained 0.41 g of mizolastine in crystalline form A, confirmed by PF, IR and DSC. KF: 0.1%.

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Example 16 Solubility of crystalline forms A and B in ethanol

Example 16A

(30ºC / 24 h)

A mixture of 500 mg of mizolastin forms Crystalline A and 10 mL of ethanol was maintained at 30 ° C for 24 hours, after which a 1 mL sample of the solution was taken crystal free As a result of the valuation of this dissolution in HPLC it was estimated that the amount of dissolved mizolastin It was 101 mg.

A mixture of 500 mg of mizolastin forms crystalline B and 10 mL of ethanol was maintained at 30 ° C for 24 hours, in exactly the same conditions described above, after which a 1 mL sample of the solution was taken crystal free As a result of the valuation of this dissolution in HPLC it was estimated that the amount of dissolved mizolastin It was 138 mg.

Example 16B

(50ºC / 24 h)

A mixture of 500 mg of mizolastin forms Crystalline A and 10 mL of ethanol was maintained at 50 ° C for 24 hours, after which a 1 mL sample of the solution was taken crystal free As a result of the valuation of this dissolution in HPLC it was estimated that the amount of dissolved mizolastin It was 145 mg.

A mixture of 500 mg of mizolastin forms crystalline B and 10 mL of ethanol was maintained at 50 ° C for 24 hours, in exactly the same conditions described above, after which a 1 mL sample of the solution was taken crystal free As a result of the valuation of this dissolution in HPLC it was estimated that the amount of dissolved mizolastin It was 240 mg.

HPLC (CH 3 CN / KH 2 PO 4 40/60 pH = 6.8, λ = 210 nm, Kromasil 100 column, c8, 5, 15x0.46 mm).

Example 17 Crystallization of mizolastin in ethanol and with planting of the crystalline form B

A solution of 1 g of mizolastin form crystalline A in 24 mL of reflux ethanol, seeded with 50 mg of the crystalline form B and cooled slowly to about 5 ° C. The mixture was filtered, and the solid obtained was dried in a forced air stove at 60ºC to constant weight. They were obtained 0.62 g of mizolastine as a mixture of crystalline forms A and B, in a weight ratio Form A / Form B of 1/60, confirmed through PF, IR and DSC.

Example 18 Crystallization of mizolastine in ethanol / water and with planting of the crystalline form A

On a suspension of 1 g of mizolastine from crystalline form B in 9 ml of ethanol at reflux were added Slowly 3 mL of water. It was stirred at reflux for 30 minutes and 3 mL more water and slowly added to this solution then it was seeded with 50 mg of mizolastine of crystalline form A and a slight turbidity was observed.

The mixture cooled slowly to a approximate temperature of 5 ° C, was filtered and the solid obtained was dried in a forced air oven at 60 ° C until constant weight. Be obtained 0.8 g of mizolastine as a mixture of forms crystalline A and B, in a weight ratio Form A / Form B of 1 / 3.9, confirmed by PF, IR and DSC.

Claims (10)

1. A crystalline form of mizolastine, called Form A, characterized in that:

exhibits a infrared (IR) spectrum in potassium bromide tablets substantially similar to that shown in Figure 1, which has bands  significant at approximately 3500, 2900, 1646, 1569, 1508, 1458, 1399, 1371, 1313, 1281, 1242, 1225, 1159, 1142, 1029, 970, 825, 804, 743, 545, 505 cm -1;

endothermia by differential scanning calorimetry (DSC) presents a maximum of 225 ° C approximately; Y

present a X-ray diffractogram (DRX) substantially similar to that shown in Figure 3, with characteristic peaks at 5.17, 4.95, 4.32, 4.08, 3.82, and 3.44 degrees 2 theta (2?).

2. A crystalline form of mizolastine, called Form B, characterized in that:

exhibits a infrared (IR) spectrum in potassium bromide tablets substantially similar to that shown in Figure 4, which has bands  significant at 3500, 2900, 1653, 1560, 1521, 1508, 1458, 1405, 1371, 1312, 1281, 1253, 1214, 1143, 1027, 971, 824, 804, 743, 546, 516 approximately cm -1;

endothermia by differential scanning calorimetry (DSC) presents a maximum of 217 ° C approximately; Y

present a X-ray diffractogram (DRX) substantially similar to that shown in Figure 6, with characteristic peaks at 10.66, 7.80, 6.98, 6.30, 5.48, 4.81, 4.48, 4.32, 3.84, 3.74 degrees 2 theta (2?).

3. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of mizolastine, selected from Form A according to claim 1, Form B according to claim 2, and mixtures thereof, together with a pharmaceutically acceptable carrier or excipient. 4. Use of a crystalline form of mizolastine selected from Form A according to claim 1, Form B according to claim 2, and mixtures thereof, in the preparation of a appropriate medication for the treatment of conditions allergic 5. A procedure to obtain the crystalline form of mizolastin called Form A, according to the claim 1, comprising recrystallize mizolastin in a solvent organic selected from the group consisting of ethanol, toluene, xylene, ethyl acetate, acetonitrile, dimethylformamide and butan-2-ol, in the absence of water; or, alternatively recrystallize mizolastin in a solvent organic selected from the group consisting of ethanol, toluene, xylene, ethyl acetate, acetonitrile, dimethylformamide, butan-2-ol, in the presence of water, in an amount equal to or less than 8% by weight of water. 6. The method according to claim 5, comprising recrystallizing mizolastine in ethanol, in the absence of
Water. 7. Method according to claim 5, which comprises recrystallizing mizolastin in ethanol, in the presence of water, in an amount equal to or less than 8% by weight of water. 8. A procedure to obtain the crystalline form of mizolastine called Form B, according to the claim 2, comprising recrystallize mizolastin in propan-2-ol, in the absence of water; or alternatively, recrystallize mizolastin in a solvent organic selected from the group consisting of ethanol, acetonitrile, dimethylformamide and propan-2-ol, in presence of an amount of water greater than 8% by weight. 9. Method according to claim 8, which comprises recrystallizing mizolastin in ethanol, in the presence of water, in an amount between 12% and 50% by weight of Water. 10. A procedure to obtain the crystalline form of mizolastine called Form B, according to the claim 2, as a majority polymorph of a mixture which it comprises the crystalline forms of mizolastine called Form A and Form B, which comprises recrystallizing mizolastin in a solvent organic selected from the group consisting of ethanol, toluene, xylene, acetonitrile, dimethylformamide, butan-2-ol and propan-2-ol, with planting of Form B crystals.