MXPA99005620A - Method for the crystallisation of a tetrahydopyridin derivative and resulting crystalline forms - Google Patents

Abstract

The invention concerns a method for the crystallisation of a tetrahydropyridin derivative, the resulting novel crystalline forms and the pharmaceutical compositions containing, as active principle, said tetrahydropyridin derivative in a predetermined crystalline form.

Description

PROCEDURE FOR CRYSTALLIZATION OF A DERIVATIVE OF TETRAHYDROPYRIDINE AND CRYSTAL FORMS RESULTANTS DESCRIPTION OF THE INVENTION The present invention relates to a process for the crystallization of a tetrahydropyridine derivative, to the new crystalline forms thus obtained and to a pharmaceutical composition containing, as an active principle, said tetrahydropyridine derivative under a certain crystalline form. More particularly, the present invention relates to a process for the crystallization of 1- [2- (2-naphthyl) tyl] -4- (3-trifluoro-et-phenyl) -l, 2,3,6-tetrahydropyridine hydrochloride. , to three crystalline forms of this product, to a defined mixture of two of these three forms, as well as to a pharmaceutical composition containing one of said forms or a mixture of two of them. 1- [2- (2-Naphthyl) ethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine, hereinafter referred to by its code number SR 57746, and its pharmaceutically acceptable salts REF .: 30352 were described for the first time in EP 0 101 381 as anorexigenic agents and, then, as anti-anxiety suppressants (US-5,026,716), anticonstipating agents (US 5,109,005), neurotrophics (US 5,270,320), anti- free radicals (US 5,292,745) and cardioprotectants (US 5,378,709). In EP 0 101 381, SR 57746 is described in the form of hydrochloride, hereinafter referred to as SR 57746 A, and its salt was used in preclinical and clinical trials in healthy volunteers. SR 57746 A, according to this document, is isolated by crystallization from ethanol, particularly from absolute ethanol. In preclinical trials, particularly in animal pharmacology and toxicology tests, SR 57746 A has shown constant activity and behavior. Likewise, far-kinematic studies in animals have given constant and reproducible results. In contrast, during clinical studies in healthy volunteers (Phase I), it has been shown that SR 57746 A has a high variability in plasma concentrations and in the pharmacodynamic effects of the active principle. In the first clinical trials in patients suffering from very serious diseases, particularly amyotrophic lateral sclerosis, the dose of SR 57746 A was kept very low, namely 2 mg / day and at this dose the product has shown to be promising (W. G. Bradley, presentation entitled "New drugs for a yotrophic lateral sclerosis," meeting of the American Academy of Neurology, March 23-30, 1996, pages 240-23 / 240/28). It has also been found that in the preparation of larger quantities of SR 57746 A according to the isolation procedure described in EP 0 101 381 it has not been possible to obtain a product with the constant characteristics that allows to solve the drawbacks observed during the studies Phase I clinics. More particularly, it has been found that according to the isolation procedure described in EP 0 101 381 an SR 57746 A composed of crystals whose size is not constant and, particularly, is greater than 150 micrometers is obtained. , more particularly it is 150-600 micrometers for at least about 75% of the crystals. Furthermore, it has been found that by operating according to the method described in EP 0 101 381, an SR 57746 A composed in at least 3 different forms is obtained, as demonstrated by differential calorimetric analysis. It has finally been found that in the different batches of manufacture of SR 57746 A the respective ratios of the different forms are not constant, which makes it difficult to master the characteristics of the raw material for the manufacture of pharmaceutical compositions. It has now been found that by effecting the crystallization of SR 57746 A under convenient and constant conditions in terms of solvent, stirring speed and cooling rate, it is possible to isolate the compound under three different crystalline forms or in the form of a mixture of two of these three forms in fixed and reproducible relationships. More particularly, it has been found that: by cooling without stirring a solution of SR 57746 A in an ethanol / concentrated hydrochloric acid mixture, Form I of SR 57746 A is obtained; cooling a solution of SR 57746 A in absolute ethanol or in an ethyl acetate / water mixture under controlled conditions of cooling speed and stirring speed, Form II of SR 57746 A is obtained; by cooling a solution of SR 57746 A in dimethylsulfoxide, Form III of SR 57746 A is obtained; cooling a solution of SR 57746 A in an ethanol / water mixture, a mixture of Form I and Form III is obtained in fixed and reproducible proportions. It has also been found that these new crystalline forms, alone or in fixed mixtures of two of them, are absorbed in a uniform and reproducible manner and allow to easily establish the optimum dose of the active principle. In addition to the improvements at the far acocinetic and pharmacodynamic level, the fact of being able to master the reproducibility of the composition under the crystalline form of SR 57746 A is very advantageous considering the commercialization of the medicine. It has finally been found that when new crystalline forms or mixtures of two of them are formed by crystals of very small size, particularly if they are micronized, the activity of the active principle increases substantially and its absorption is uniform and constant, which allows at the same time the administration of small doses with very good therapeutic response and the total control of the potential side effects. The attached figures show the thermograms obtained by submitting Form I, Form II, Form III and a mixture Form I / Form III in a ratio 65.7 / 34.3 to a differential calorimetric analysis. Figure 1 shows the thermogram of Form I of SR 57746 A, prepared according to Example 1, obtained by differential calorimetric analysis from 50 ° C to 180 ° C. This thermogram shows a solid-solid transition temperature of 148-149 ° C. Figure 2 shows the thermogram of Form II of SR 57746 A, prepared according to Example 2, obtained by differential calorimetric analysis of 50 ° C to 180 ° C. This thermogram shows a solid-to-solid transition temperature of 153-155 ° C. Figure 3 shows the thermogram of the Form III of SR 57746 A, prepared according to Example 3, obtained by differential calorimetric analysis from 50 ° C to 180 ° C. This thermogram shows a solid-solid transition temperature of 141-142 ° C.

Figure 4 shows the thermogram of the mixture of Form I / Form III of SR 57746 A, prepared according to Example 4, obtained by differential calorimetric analysis of 50 ° C to 180 ° C. This thermogram shows the solid-solid transition temperatures of the two forms. Thus, according to one of its aspects, the subject of the present invention is a process for the crystallization of l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1, 2, 3 hydrochloride. , 6-tetrahydropyridine, characterized in that: (a) said compound is dissolved by heating in a solvent selected from the alkanols, from 1 to 3 carbon atoms, the ketones from 3 to 6 carbon atoms, the dimethylsulfoxide or the acetate of ethyl, said solvent optionally containing from 5 to 30% by volume of water or aqueous hydrochloric acid; (b) the solution thus obtained is cooled to -10 / + 10 ° C at a rate of 3 to 100 ° C / hour, under an agitation of 0 to 600 rev / inuto; and (c) the product thus obtained is isolated and, if necessary, micronized. The process of the present invention is carried out in accordance with the classical operating mode of crystallization techniques, but the type of solvent, the rate of cooling, the absence or the presence of water as well as the speed of agitation constitute essential parameters for the obtaining, in a reproducible manner, one crystal form more than another or, always reproducibly, a mixture of two forms in fixed relations. In step (a), an l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, for example, the crude product obtained according to the method described in EP 0 101 381, it is heated, preferably under reflux, in the chosen solvent, optionally in the presence of water. The presence of water may prove useful to completely solubilize SR 57746 A., for example, in methanol and in ethanol the product is completely solubilized to a reasonable concentration (for example 15-150 g / 1), while, at the same concentrations, it is not completely solubilized in acetone, methyl ethyl ketone, isopropanol and ethyl acetate. ethyl. In these solvents, it is sufficient to add 5 to 30% of water so that the complete solubilization takes place at the reflux temperature. The percentage of water must therefore not be too high to avoid an excess of solubilization and a loss of final product. According to an advantageous operating mode, the solvent used is chosen from the mixtures (v / v) methanol / water from 100/0 to 70/30, ethanol / water of 100/0 to 70/30, acetone / water 95/5 to 70/30, methyl ethyl ketone / water 95/5 to 80/20, ethyl acetate / water 95/5 to 70/30 or dimethylsulfoxide. The concentration of SR 57746 A in the chosen solvent depends, as mentioned above, on the solubility. It can be about 15-100 g / 1 for ethyl acetate / water mixtures at 150-300 g / 1 for ethanol and for ethanol / water mixtures. Advantageously, SR 57746 A is dissolved at a concentration of 5-150 g / 1, preferably 100-150 g / 1 in ethanol or in an ethanol / water mixture approximately 90/10 or in methanol, or at a concentration of about 60 g / 1 in a mixture of acetone / water about 90/10, 100-125 g / 1 in a methyl ethyl ketone / water mixture about 95/15 or about 15 g / 1 in a mixture of ethyl acetate / water 90 / 10 Under these conditions, the solubilization in the refluxing solvent is total.

In step (b), the solution thus obtained is cooled, possibly under stirring, with a control of the cooling rate and, if there is agitation, the stirring speed since obtaining a suitable crystalline form depends largely on of these two parameters. When the crystallization is carried out with stirring, a mobile stirring device (also referred to as "impeller") is preferably used, which allows a rotational movement of the liquid as a whole, whose rotation diameter is between 4/5 and 2 / 5 of the reactor used. The cooling rate is regulated with a temperature gradient that can go from 10 Cf to 3 ° C per hour. Obtaining a particular crystalline form, rather than a mixture in fixed proportions of two forms, depends on the two parameters indicated above at the same time, in a given solvent, it being understood that the agitation speed generally varies in direct relation to the speed Cooling. In step (c), the product thus crystallized is isolated according to conventional techniques and, if necessary, micronized.

The isolation of the product can provide, for example, the drying of the compound obtained; it has been demonstrated that the drying step, whether carried out in an oven or in a stirred dryer, does not modify the crystalline structures obtained for crystallization. Choosing the appropriate conditions for stages (a) and (b), in stage (c) four different species of SR 57746 A can be isolated, namely Form I, Form II, Form III or the mixture I / III, whose essential characteristics can be determined by differential calorimetric analysis ("DSC", of the English Differential Scanning Calorimetry) that gives, by means of the thermograms obtained with a Perkin-Elmer calorimeter under well-defined conditions: the solid-solid transition temperature; and the enthalpy linked to this transition. The differential calorimetric analysis was performed using a Perkin-Elmer DSC7 device whose contrast was made in relation to the fusion endotherms of indium or lead and cyclohexane. For this analysis, 3 to 6 mg of product were used in a cup-aluminum mounted and perforated on the lid, in a temperature zone of 50 to 180 ° C at a heating rate of 10 ° C / minute, using the nitrogen as a sweep gas. The solid-solid transition temperature and the transition enthalpy are sufficient essential characteristics to identify each crystalline form or mixtures of two such forms. Said shapes can also be characterized by diffractometry of the powder X-rays. The diffraction profile of the X-rays of the pà © lvo (Bragg 2? Diffraction angles) was established with a Siemens 500 TT diffractometer with a 40 kV generator, monochromator back, Cu kx 1 source, silicon carrier and in a scanning domain from 4 ° to 40 ° at a rate of Io per minute. According to an advantageous method, step (a) is carried out by refluxing SR 57746 A in an ethanol / hydrochloric acid mixture in a ratio comprised between 95/5 and 70/30 until complete dissolution and step (b) is carried out by cooling the solution thus obtained with a temperature gradient of 3 to 100 ° C per hour up to about 4 ° C, without agitation. According to an advantageous operating mode, in step (c) a crystalline form of SR 57746 A is isolated, hereinafter called "Form I", characterized in that it has: - a solid-solid transition temperature of 148.4 ± 1.6 ° C - a transition enthalpy of 26.4 ± 1.1 J / g. Form I of SR 57746 A having the features indicated above constitutes a further aspect of the present invention. This new crystalline form has also been analyzed by diffraction of the X-rays of the powder. The qualitative study of the diffractograms has allowed to establish that Form I presents characteristic stripes (2?) At: 9.9 ± 0.3 ° - 14.8 ± 0.3 ° 20.8 ± 0.3 ° (intensity 100). Form I is also obtained when, in step (b), the solution is cooled and left 8-15 hours at 0-5 ° C, always without agitation. According to another advantageous operating mode, step (a) is carried out by heating under reflux in absolute ethanol or in an ethyl acetate / water mixture of 95/5 to 75/15 until complete dissolution, SR 57746 A being present, in this solution at a concentration of 10-80 g / 1, preferably 70 g / 1 in the ethyl acetate / water mixture or 5-150 g / 1 in absolute ethanol. Step (b) according to this advantageous operating mode, is effected by cooling the reflux temperature to about 5 ° C with a temperature gradient of 100 to 30 ° C per hour and a stirring speed of 100 to 600 rev / minute . In step (c), another crystalline form, named "Form II", is thus isolated, characterized in that it presents: +++++ a solid-solid transition temperature of 153.9 ± 1.1 ° C, a transition enthalpy of 24.1 ± 1.0 J / g. Form II of SR 57746 A having the features indicated above constitutes another aspect of the present invention. This new crystalline form was also analyzed by diffraction of the X-rays of the powder. The qualitative study of diffractograms has made it possible to establish that Form II has characteristic stripes (2?) At: 14.5 ± 0.3 ° (intensity 100) 19.3 ± 0.3 ° - 20.4 ± 0.3 °.

According to another advantageous operating mode, step (a) is carried out by refluxing SR 57746 A in dimethylsulfoxide until complete dissolution and step (b) is carried out by cooling the solution thus obtained with a temperature gradient of 3 to 100 °. C per hour and a stirring speed of 0 to 600 rev / minute. In step (c), another crystalline form is thus isolated, hereinafter referred to as "Form III", characterized in that it has: a solid-solid transition temperature of 141. 2 ± 2 ° C a transition enthalpy of 17.6 ± 0.5 J / g. Form III of SR 57746 A having the features indicated above constitutes another aspect of the present invention. According to another particularly advantageous operating mode, step (a) is carried out by heating SR 57746 A in an ethanol / water mixture of 95/5 to 70/30, preferably 90/10 to 85/15, until complete dissolution , and step (b) is carried out by cooling the temperature with a temperature gradient of 5 to 30 ° C per hour, advantageously up to 5 ° C with a temperature gradient of 10 to 20 ° C per hour, preferably 10 ° C per hour and at a stirring speed of 0 to 600 rev / minute, advantageously 200 to 400 rev / minute, preferably 400 rev / minute. Unexpectedly, it has been found that, in step (c), a mixture of Form I / Form III is isolated in a reproducible manner in the weight ratios of 80/20 to 60/40, advantageously 70/30 to 65. / 35, preferably approximately 66/34, as demonstrated by differential calorimetric analysis. This mixture is formed by particles having a diameter of less than 150 micrometers. Forms I, II and III of SR 57746 A as well as the mixture of Forms I and III can be micronized so as to obtain a pharmaceutical active principle having a granulometry of less than 50 microns, advantageously less than 30 microns, preferably for at least 80% of the particles, less than 10 micrometers. The icronization can be carried out in a conventional apparatus that allows to obtain microcrystals having a size smaller than 50 micrometers, for example, in an Alpine 200 AS micronizer, introducing the SR 57746 A in the micronization chamber (diameter of 200 mm) to the speed of 15 to 50 kg / hour and a working pressure of 1 to 6.5 bar and recovering the product in a filter bag. The crystalline forms I, II, III of SR 57746 A, as well as the mixtures of Forms I and III in the ratios of 80/20 to 60/40, advantageously of 70/30 to 65/35, preferably of about 66 / 34, micronized, constitute a particularly advantageous aspect of the present invention. The availability of well-defined forms of SR 57746 A or of a fixed mixture Form I / Form III makes it possible to prepare pharmaceutical compositions having a constant and reproducible composition. Furthermore, obtaining a product having a fine granulometry, for example, by micronization, allows constant activity to substantially reduce the effective doses to obtain the same therapeutic result. More particularly, it has been shown that the icrocrystalline form not only makes it possible to reduce the amount of doses present in the pharmaceutical compositions but, above all, makes it possible to make oral absorption uniform and thus have a constant therapeutic response in each patient to whom it was administered. the product fasting or with food. A study concerning the determination of the absorption in vi tro of SR 57746 A - micronized Form I / III mixture was carried out using the mono-layer model CACO-2. This test, widely used as an intestinal epithelial model to predict drug absorption (P. Artusson, Crit. Rev. Ther.Drug, 1991, 8: 305-330) has allowed to demonstrate the significant differences of dissolution and permeability of SR 57746 A - micronized Form I / III mixture in relation to SR 57746 A obtained according to EP 0 101 381. The results show that, in the medium used (Hank's solution supplemented with 10% fetal calf serum and taurocholic acid), the dissolution and permeability rates are significantly different for SR 57746 A - micronized Form I / III mixture in relation to SR 57746 A obtained according to EP 0 101 381. More particularly, it has been shown that the dissolution and the permeability are normalized - namely, made uniform - after micronization. Thus, according to another of its aspects, the present invention has as its object a pharmaceutical composition containing, as active principle, 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) hydrochloride. ) -1, 2, 3, 6-tetrahydropyridine under a possibly micronized crystalline form selected from Form I, Form II, Form III as defined above, and Form I / Form III mixtures at ratios of 80 / 20 to 60/40, advantageously from 70/30 to 65/35, preferably from approximately 66/34. The administration of crystalline forms of the invention can be conveniently carried out orally, parenterally, sublingually or transdermally. The amount of active principle to be administered depends on the nature and severity of the conditions to be treated as well as the weight of the patients. However, the amount of active ingredient present in the dosage unit may be about 10 mg (calculated on a free base) for the non-micronized product and may be 0.1 to 5 mg, advantageously 0.5 to 3 mg, preferably 2 mg (calculated on a free basis for the micronized product) Preferred unit doses will generally comprise 0.5, 1, 1.5, 2, 2.5 or 3 mg (calculated on a free basis) of the micronized product.

These unit doses will normally be administered once or several times per day, for example once or twice a day, with the overall dose in man varying between 0.5 and 20 mg per day, advantageously between 1 and 10 mg per day (calculated on the basis of free) for the non-micronized product and from 0.2 to 10 mg per day, advantageously between 1 and 6 mg per day (calculated on free base), for the micronized product. In the unit forms of the pharmaceutical compositions of the present invention, the active ingredient is administered, preferably mixed with conventional pharmaceutical carriers, to animals and humans for the treatment of the diseases indicated in particular in US Pat. Nos. 5,026,716 , US 5,109,005, US 5,270,320, US 5,292,745 and US 5,378,709, in particular for the treatment of neurodegeneration, particularly amyotrophic lateral sclerosis. Suitable unit administration forms preferably comprise oral forms such as optionally scored tablets, capsules, powders, granules, sublingual and buccal administration forms, and transdermal administration forms can also be prepared using the new crystalline forms . When preparing a solid composition in the form of tablets, the active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets of sucrose or other suitable substances can be coated or they can also be treated in such a way that they have a prolonged or delayed activity and that they release in a continuous manner a predetermined quantity of active principle. A capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the obtained mixture into the soft or hard capsules. The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives. In the pharmaceutical compositions according to the present invention, the active principle may also be in the form of inclusion complex in cyclodextrins, their ethers or their esters.

The following examples illustrate the invention, EXAMPLE 1 A mixture of 19.5 g of crude l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine hydrochloride, 95 ml of absolute ethanol and 4.65 ml of 37% hydrochloric acid is heated to reflux under stirring until complete dissolution, then allowed to cool, always under agitation. When the first crystals begin to form (towards 63 ° C), stirring is stopped and the reaction mixture is maintained at 0-5 ° C overnight. After filtration, the product is again dissolved twice in 30 ml of absolute ethanol, then dried overnight at 40 ° C under vacuum. Under these conditions, 12.8 g of Form I of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine hydrochloride (SR 57746 A- was obtained. Form I). In differential calorimetric analysis, SR 57746 A - Form I obtained in this preparation presented: a solid-solid transition temperature of 148-149 ° C a transition enthalpy of 26.4 J / g. The corresponding thermogram is shown in Figure 1. In the powder X-ray diffraction analysis, with a Siemens 500 TT diffractometer in the conditions indicated above, SR 57746 A - Form I obtained in this preparation has the characteristic stripes ( 2 angles of Bragg) to 9.8 °; 14.7 ° and 20.7 ° (relative intensity: 100). The X-ray powder diffraction profile (diffraction angles) of SR 57746 A Form I of this preparation is given by the significant dashes summarized in Table 1, with the relative intensity, expressed as a percentage in relation to the longest line. intense TABLE 1 SR 57746 A - Form I EXAMPLE 2 In a Mettler RC1 calorimetric reactor equipped with an 8 cm diameter paddle stirrer, a mixture of 70 g of l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethyl phenyl) - hydrochloride 1,2,3,6-tetrahydropyridine crude and 1 1 of absolute ethanol is heated to reflux until complete dissolution of the product. The solution thus obtained is cooled with a cooling rate of 80 ° C per hour and a stirring speed of 500 rev / minute up to 10 ° C. The precipitate thus obtained is filtered and dried overnight at 45 ° C under vacuum. Under these conditions, Form II of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride (SR 57746 A - Form II) has been obtained. ). In the differential calorimetric analysis, SR 57746 A - Form I obtained in this preparation presented: - a solid-solid transition temperature of 153-155 ° C, a transition enthalpy of 24.1 J / g. The corresponding thermogram • is shown in Figure 2. In the powder X-ray diffraction analysis, with a Siemens 500 TT diaphragmometer in the conditions indicated above, SR 57746 A - Form II obtained in this preparation presents the stripes characteristics (angles 2? Bragg) to 14.3 ° (relative intensity: 100), 19.2 ° and 20.5 °. The X-ray powder diffraction profile (diffraction angles) of SR 57746 A Form II of this preparation is given by the significant dashes summarized in Table 2, with the relative intensity, expressed as a percentage in relation to the longest line. intense TABLE 2 EXAMPLE 3 A mixture of 2 g of crude l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride and 50 ml of dimethyl sulfoxide is heated to reflux until complete dissolution, the mixture is allowed to cool overnight, then the crystalline product is recovered and dried under vacuum at 45 ° C overnight.

Under these conditions, Form III is obtained from 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride (SR 57746 A - Form III) . In the differential calorimetric analysis, SR 57746 A - Form III obtained in this preparation presented: a solid-solid transition temperature of 141-142 ° C - a transition enthalpy of 17.6 J / g. The corresponding thermogram is shown in Figure 3.

EXAMPLE 4 A mixture of 100 g of l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride in 1 liter of ethanol / water mixture 90/10 is heated to reflux with stirring until complete dissolution of the product. The solution thus obtained is cooled from the reflux temperature to 5 ° C under stirring with paddle at 400 rev / minute at a cooling rate of 10 ° C / hour. The crystalline product thus obtained is filtered and dried at 45 ° C under vacuum overnight.

Under these conditions, 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine hydrochloride in the form of mixture Form I / Form III has been obtained , in a relation 65.7 / 34.3 (SR 57746 A - Form I / III). In differential calorimetric analysis, SR 57746 A - Form I / III obtained in this preparation presents a thermogram consigned in Figure 4 that shows only the two characteristic peaks corresponding to Forms I / III.

EXAMPLES 5 and 6 Operating as described in Example 2, in two different preparations the cooling rate and the stirring speed have been varied in the following manner: cooling at 100 ° C hour and stirring at 600 rev / minute (Ex. 5); cooling at 30 ° C / hour and stirring at 300 rev / minute (Ex 6); Under these conditions SR 57746 A - Form II was obtained. It has therefore been found that operating in absolute ethanol at a concentration of 70 g / 1, obtaining Form II depends on the cooling rate and the speed of agitation according to a linear equation of the type y = ax + b. To obtain Form II under these conditions, the equation is as follows: Rmax = 4.23.V + 170.51 in which Rma is the stirring speed in rev / minute and V is the cooling rate in ° C / hour. Consequently, in order to obtain Form II, for a given cooling speed, the stirring speed must be less than or equal to EXAMPLE 7 A mixture of 15 g of l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride crude in 1: 1 mixture of ethyl acetate ethyl / water 90/10 is heated to reflux until complete dissolution of the product under agitation with a paddle stirrer of 8 cm in diameter. The solution thus obtained is cooled to 60 ° C per hour with a stirring speed of 150 rev / minute, up to 5 ° C, then the precipitate thus obtained is filtered and dried under vacuum. This gives the SR 57746 A Form II identical to the product c- held in accordance with Example 2.

EXAMPLES 8-11 In four different preparations, crude 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride in a mixture of ethyl acetate / water 92/8 at a concentration of 70 g / 1 (reaction volume: 1.3 1) is heated to reflux in an RC 1 reactor coupled with a particle monitor PARTEC! R) 100 from the firm Lasentec and equipped with an agitator of pallet of 8 cm in diameter. After completing the solution, in all four preparations the solution was cooled under the following conditions: cooling at 100 ° C / hour and stirring at 400 rev / minute (Ex. 8); - cooling at 80 ° C / hour and stirring at 300 * rev / minute (Ex 9); cooling at 50 ° C / hour and stirring at 200 rev / minute (Ex 10); cooling at 30 ° C / hour and stirring at 100 rev / minute (Ex 11). Under these conditions SR 57746 A - Form II was obtained. It has been found that operating in a mixture of ethyl acetate / water 92/8 at a concentration of 70 g / 1, obtaining the Form II depends on the rate of cooling and the speed of agitation according to the following equation linear: Rmax = 4.14.V - 18.9 in which Rma? is the stirring speed in rev / minute and V is the cooling rate in ° C / hour. In order to obtain Form II, it is necessary that, for a given cooling speed, the stirring speed be less than or equal to Rma? - EXAMPLE 12 The hydrochloride of crude l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine in a mixture is heated to reflux with stirring until complete dissolution. of acetone / water 90/10 at a concentration of 60.6 g / 1. By operating below as described in Example 4, SR 57746 A - Form I / III is obtained in an 80/20 ratio.

EXAMPLE 13 The crude l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride in methanol is heated to reflux with stirring until complete dissolution. a concentration of 100 g / 1. By then operating as described in Example 4, SR 57746 A - Form I / III is obtained in an 80/20 ratio identical to the product of Example 12.

EXAMPLE 14 The crude hydrochloride of crude l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine in a mixture is heated to reflux with stirring. of ethanol / water 70/30 at a concentration of 100 g / 1. By operating below as described in Example 4, SR 57746 A - Form I / III is obtained in a ratio 65.7 / 34.3 identical to the product of Example 4.

EXAMPLE 15 A micronizer ALPINE 200 AS 24 kg of SR 57746 A - Form I / III, described in Example 4, is introduced into the micronization chamber (diameter 200 mm) at a speed of 25 kg / hour and at a pressure of 6.5 bar work and the micronized product is recovered in a filter bag. Thus, SR 57746 A - Form I / III having a particular distribution according to which all of the particles have a size of less than 20 micrometers and 85% of the particles have a size of less than 10 micrometers is obtained. The differential calorimetric analysis of the micronized product thus obtained shows that the transition temperatures are not affected by micronization. These transitions are of the solid-solid type. SR 57746 A degrades before melting, which starts at 250 ° C.

EXAMPLE 16 The pharmaceutical composition contains, as an active ingredient, SR 57746 A - Form I / III (micronized) according to Example 15 indicated above: Active principle 2192 mg Corn starch 141,218 mg Colloidal anhydrous silica 0.200 mg Magnesium stearate 0.400 mg The active principle is sieved to 0.2 mm, then premixed with the excipients. This mixture is sieved at 0.315 mm, mixed again, then sieved again at 0.315 mm. After a last mixture, the composition is introduced into gelatin capsules No. 3, at a rate of 170 mg of composition containing an amount of SR 57746 A - Form I / III corresponding to 2 mg of 1- [2- (2 -naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine base. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (25)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Procedure for the crystallization of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride (SR 57746 A) characterized in that: (a) it is dissolved said compound by heating in a solvent selected from alkanols, from 1 to 3 carbon atoms, ketones of 3 to 6 carbon atoms, dimethylsulfoxide or ethyl acetate, said solvent optionally containing from 5 to 30% of water or of aqueous hydrochloric acid; (b) the solution thus obtained is cooled to -10 / + 10 ° C at a rate of 3 to 100 ° C / hour, under an agitation of 0 to 600 rev / minute; and (c) the product thus obtained is isolated and, if necessary, micronized.

2. Process according to claim 1, characterized in that step (a) is carried out by refluxing SR 57746 A in a mixture of ethanol / hydrochloric acid in a ratio comprised between 95/5 and 70/30 until complete dissolution, the step (b) is carried out by cooling the solution thus obtained with a temperature gradient of 3 to 100 ° C per hour up to about 4 ° C, without stirring and in step (c) Form I is isolated from the hydrochloride of 1- [2] - (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine.

3. Process according to claim 1, characterized in that step (a) is carried out by refluxing SR 57746 A in absolute ethanol or a mixture of ethyl acetate / water 95/5 to 75/15 until complete dissolution, being present said compound in that solution at a concentration of 10-80 g / 1 in the ethyl acetate / water mixture or 5-150 g / 1 in absolute ethanol; step (b) is carried out by cooling the reflux temperature to about 5 ° C with a temperature gradient of 100 to 30 ° C per hour and a stirring speed of 100 to 600 rev / minute and, in step (c) ), Form II is isolated from l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride.

4. Process according to claim 1, characterized in that step (a) is carried out by refluxing SR 57746 A in dimethylsulfoxide until complete dissolution, step (b) is carried out by cooling the solution thus obtained with a temperature gradient of 3 to 100 ° C per hour and a stirring speed of 0 to 600 rev / minute and, in step (c), Form III of 1- [2- (2-naphthyl) ethyl] -4- hydrochloride ( 3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine.

5. Process according to claim 1, characterized in that step (a) is carried out by refluxing SR 57746 A in an ethanol / water mixture from 95/5 to 70/30 until complete dissolution, step (b) is carried out cooling the solution thus obtained with a temperature gradient of 5 to 30 ° C per hour and a stirring speed of 0 to 600 rev / minute and, in step (c), the mixture of Form I / III of the hydrochloride is isolated of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine in a ratio of 80/20 to 60/40.

6. Method according to claim 5, characterized in that in step (a) a mixture of ethanol / water of 90/10 is used, step (b) is carried out by cooling the solution thus obtained to 5 ° C with a temperature gradient from 10 to 20 ° C per hour and a stirring speed of 200 to 400 rev / minute and, in step (c), the mixture of Form I / III of l- [2- (2-naphthyl) hydrochloride is isolated. ) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine in a ratio of 70/30 to 65/35.

7. Method according to claim 6, characterized in that in the step (b) the temperature gradient is 10 ° C per hour and the stirring speed is 400 rev / minute and, in step (c), the mixture of form I / III is isolated from the hydrochloride of 1- [2] - (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine in a ratio of approximately 66/34.

8. Method according to one of claims 1 to 7, characterized in that a mobile paddle stirrer is used.

9. Form I of l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride which can be obtained according to the process of claim 2 .

10. Form II of l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride which can be obtained according to the process of claim 3 .

11. Form III of l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride which can be obtained according to the process of claim 4 . ß

12. Mixture of Form I and Form III of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride which can be obtained in accordance with with the method of one of claims 5 to 7.

13. Form I of l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, characterized in that it has: a solid-solid transition temperature of 148. 4 ± 1.6 ° C a transition enthalpy of 26.4 ± 1.1 J / g.

14. Form I according to claim 13, characterized in that its diffractogram of the X-rays of the powder presents the characteristic lines (angles 2? Of Bragg) to: * 9.9 + 0.3 ° * 14.8 ± 0.3 ° * 20.8 ± 0.3 ° (intensity 100) ).

15. Form II of l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, characterized in that it has: * a solid-to-solid transition temperature of 153.9 ± 1.1 ° C * a transition enthalpy of 24.1 ± 1.0 J / g.

16. Form II according to claim 15, characterized in that its diffractogram of the X-rays of the powder presents the characteristic lines (angles 2? Of Bragg) to: * 14.5 ± 0.3 ° (intensity 100) * 19.3 ± 0.3 ° * 20.4 ± 0.3 °.

17. Form III l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, characterized in that it has: * a solid-to-solid transition temperature of 141 ± 2 ° C * a transition enthalpy of 17.6 ± 0.5 J / g.

18. Crystalline form according to any one of claims 9 to 17, characterized in that it is micronized.

19. Mixture of Form I according to claim 13 or 14 and of Form III according to claim 17 in a Form I / Form III ratio of 80/20 to 60/40.

20. Mixture according to claim 19, in a Form I / Form III ratio of 70/30 to 65/35.

21. Mixture according to claim 20, in a Form I / Form III ratio of about 66/34.

22. Mixture according to one of claims 19 to 21, characterized in that it is micronized.

23. Pharmaceutical composition containing, as an active ingredient, l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride in crystalline form, optionally micronized , chosen between Form I, Form II, Form III and mixtures Form I / Form III according to one of claims 9 to 21.

24. Composition according to claim 23, characterized in that the active ingredient is a mixture according to claim 22, in the form of a dosage unit.

25. Composition according to claim 24, characterized in that each dosage unit contains an amount of micronized active principle corresponding to a dose chosen between 0.5, 1, 1.5, 2, 2.5 or 3 mg of free base.