SK82899A3 - 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

METHOD OF CRYSTALLIZATION OF TETRAHYDROPYRIDINE

DERIVATIVE, CRYSTALLINE FORMS OBTAINED AND PHARMACEUTICAL <> h

ORSA HOM.

Technical field

The invention relates to a process for the crystallization of a tetrahydropyridine derivative, to novel crystalline forms obtained by this process and further, to a pharmaceutical composition comprising the tetrahydropyridine derivative in a given crystalline form as the active substance.

In particular, the invention relates to a process for crystallizing 1- [2- (2-naphthyl) ethyl] -4 (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, three crystalline forms of the product, a defined mixture of two of the three forms, and a pharmaceutical composition comprising one of these forms or a mixture of the two.

BACKGROUND OF THE INVENTION

- [2- (2-naphthyl) ethyl] -4- (3-trifluoroethylphenyl) -1,2,3,6 tetrahydropyridine hydrochloride, hereinafter referred to as SR code 57746, and its pharmaceutically acceptable salts were first described in European U.S. Patent No. 5,768,516; EP 0 101 381 as anorexigenic agents and subsequently as anxiety suppressants (U.S. Patent No. 5,026,716), anticonstitution agents (U.S. Patent No. 5,109,005); No. 5,270,320), free radical acceptors (U.S. Patent No. 5,292,745), and cardioprotective agents (U.S. Patent No. 5,387,709). EP 0 101 381 discloses SR 57746 in the form of the hydrochloride, hereinafter referred to as SR 57748 A, which salt has been used in preclinical and clinical trials in healthy volunteers. According to this document, SR 57746 was isolated by crystallization from ethanol, preferably from absolute ethanol.

31238 / H

In preclinical tests, especially in animal pharmacological and toxicological tests, SR 57746 A showed constant activity and behavior. Similarly, animal pharmacokinetic studies provided constant and reproducible results.

In contrast, in clinical trials conducted in healthy volunteers (Phase I), SR 57746 A showed high variability in plasma concentrations as well as pharmacodynamic effects of the active substance.

In the first clinical trials conducted on patients suffering from very serious diseases, in particular amyotrophic lateral sclerosis, the dose of SR 57746 A was kept at a very low level, namely 2 milligrams / day, which proved to be promising (see WG Bradley). , New drugs for amyotrophic lateral sclerosis, American Academy of Neurology meeting, 23-30 March, 1996, pages 240 23/240-28.

Furthermore, it has been found that the preparation of larger amounts of SR 57746 A by the isolation procedure described in EP 0 101 381 fails to satisfactorily provide a product with constant characteristics that would overcome the disadvantages mentioned in relation to phase I clinical trials.

In particular, it has been found that by means of the isolation process described in EP 0 101 381, SR 57746 A is obtained, which consists of crystals whose size is not constant and exceeds 150 microns, at least 75% of the crystals having a size ranging from 150 micrometers to 600 micrometers.

Furthermore, it has been found that SR 57746 A obtained by the method described in EP 0 101 381 consists of at least three different forms, as demonstrated by the differential scanning calorimetry technique.

Finally, it was found that the ratios of these different forms do not reach constant values in different production batches of SR 57746 A, which

31238 / H complicates the control of the characteristics of the starting material for the manufacture of pharmaceutical compositions.

SUMMARY OF THE INVENTION

It has been found that by crystallizing SR 57746 A under suitable and constant conditions in terms of solvent, stirring rate and cooling rate, it is possible to isolate the compound in three different crystalline forms or as a mixture of two of the three forms in fixed and reproducible form. ratios.

In particular, the following has been found according to the present invention:

Form I of SR 57746 A is obtained by cooling a solution of SR 57746 A in ethanol / concentrated hydrochloric acid without stirring;

Form II of SR 57746 A is obtained by cooling a solution of SR 57746 A in absolute ethanol or ethyl acetate / water under controllable conditions in terms of cooling rate and stirring rate;

Form III of SR 57746 A is obtained by cooling a solution of SR 57746 A in dimethylsulfoxide; and

a mixture of Form I and Form III in fixed and reproducible proportions is obtained by cooling a solution of SR 57746 A in an ethanol / water mixture.

It has also been found that these new crystalline forms, either alone or in solid mixtures of two of these forms, are absorbed in a uniform and reproducible manner, making it easier to set the optimum dose of the active ingredient. Apart from improving pharmacokinetic and pharmacodynamic characteristics, the ability to control the reproducibility of the SR 57746 A composition in crystalline form is very beneficial in terms of the marketing of pharmaceutical products.

31238 / H

Finally, it has been found that when these new crystalline forms or mixtures of two of these forms are very small crystals, preferably micronized crystals, the activity of the active substance increases markedly and its absorption is uniform and constant, allowing small doses to be administered. with very good therapeutic effect and at the same time completely control potential side effects.

Description of the drawings

The accompanying drawings show thermographic records obtained using the differential scanning calorimetry technique for analyzing Form I, Form II, Form III, and a Form I / Form III mixture at a ratio of 65.7 / 34.3.

In FIG. 1 shows a thermographic record of Form I of SR 57746 A prepared according to Example 1, wherein the thermographic record was obtained by differential scanning calorimetry in the temperature range from 50 ° C to 280 ° C. This thermographic record shows a transition temperature between two solid phases ranging from 148 ° C to 149 ° C.

In FIG. 2 shows a thermographic record of Form II of SR 57746 A prepared according to Example 2, wherein the thermographic record was obtained by differential scanning calorimetry in the temperature range of 50 ° C to 180 ° C. This thermographic record shows the transition temperature between two solid phases ranging from 153 ° C to 155 ° C.

In FIG. 3 shows a thermographic record of Form III of SR 57746 A, prepared according to Example 3, wherein the thermographic record was obtained by differential scanning calorimetry in the temperature range from 50 ° C to 180 ° C. This thermographic record shows the transition temperature between two solid phases ranging from 141 ° C to 142 ° C.

In FIG. 4 shows a thermographic record of a mixture of Form I and Form III prepared according to Example 4, wherein the thermographic record was obtained by differential scanning calorimetry in the temperature range of

31238 H ° C to 180 ° C. This thermographic record shows solid-solid transition temperatures for two different forms. Thus, one aspect of the invention relates to a process for the crystallization of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6 tetrahydropyridine hydrochloride, comprising the steps of: (a) the compound is heated by heating in a solvent selected from the group consisting of alkanols containing from one to three carbon atoms, ketones containing from three to six carbon atoms, dimethylsulfoxide and ethyl acetate, which solvent may optionally contain water or an aqueous solution of hydrochloric acid in an amount, which ranges from 5% to 30% by volume;

(b) the resulting solution is cooled to -10 ° C / + 10 ° C at a rate ranging from 3 ° C / hour to 100 ° C / hour with stirring at a rate of 0 rpm / minute to 600 rpm;

and (c) the resulting product is isolated and optionally also micronized.

The process of the invention is carried out in accordance with a conventional procedure used in crystallization techniques, but the solvent type, cooling rate, absence or presence of water and mixing rate are essential parameters for reproducible preparation of one crystalline form among other forms or for reproducible preparation of two forms in fixed proportions.

In step (a), 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) 1,2,3,6-tetrahydropyridine hydrochloride, such as the crude product obtained by the process described in EP 0 101 381 , heated in a selected solvent, which heating may optionally be carried out in the presence of water, preferably at reflux.

31238 / H

The presence of water may become significant for the complete dissolution of SR 57746 A. For example, in methanol and ethanol, this product dissolves completely at a reasonable concentration (for example, a concentration ranging from 15 grams / liter to 150 grams / liter), this does not completely dissolve the product in acetone, methyl ethyl ketone, isopropanol or ethyl acetate at these concentrations. In these solvents, it is then sufficient to add water in an amount ranging from 5% to 30% to completely dissolve at reflux temperature. However, the percentage of water must not be too high to avoid excessive dissolution and therefore loss of the final product.

In a preferred embodiment of the invention, the solvent used is selected from the following mixtures (proportions of the components in parts by volume): methanol / water: proportions of the components ranging from 100/0 to 70/30, ethanol water: proportions of the components ranging from 100 100/0 to 70/30, acetone / water: proportions ranging from 95/5 to 70/30, methyl ethyl ketone / water: proportions ranging from 95/5 to 80/20, ethyl acetate / water: proportions of components ranging from 95/5 to 70/30 and dimethylsulfoxide.

As mentioned above, the concentration of SR 57746 A in the selected solvent depends on solubility. This concentration can range from about 15 grams / liter to 100 grams / liter for ethyl acetate / water mixtures to 150 grams / liter to 300 grams / liter for ethanol and ethanol / water mixtures.

The product SR 577 46 A is preferably dissolved such that its concentration in ethanol, in a 90/10 ethanol / water / methanol mixture is in the range of 5 grams / liter to 150 grams / liter, preferably ranging from 100 grams / liter to 150 grams / liter or that its concentration in the 90/10 acetone / water mixture gives approximately 60 grams / liter or that its concentration in the 95/15 methyl ethyl ketone / water mixture is in the range of 100 grams / liter to 125 grams / liter or keep its concentration in the mixture

31238 Ή ethyl acetate / water with a 90/10 ratio gave about 15 grams / liter. The dissolution in the solvent at reflux temperature is complete under these conditions.

In step (b), the solution thus obtained is cooled, which cooling may optionally be performed with stirring; the cooling rate is monitored and, if a mixing device is used, the stirring rate is also monitored, since the preparation of a suitable crystalline form depends largely on these two parameters.

When this crystallization is carried out during stirring, preferably a paddle stirrer (also referred to as a high speed stirrer) is used to allow all the liquid to rotate, the diameter of rotation of the stirring device being selected to be within the range of 4/5 to 2/5 of the reactor diameter used.

The cooling rate is controlled so that the temperature gradient ranges from 100 ° C / hour to 3 ° C / hour.

The production of a certain crystalline form, rather than a mixture of the two forms in fixed proportions, depends on the simultaneous action of the above two parameters in a given solvent, with the stirring rate generally varying as a proportional function of the cooling rate.

In step (c), the crystalline product thus obtained is isolated using conventional techniques and optionally also micronized.

Isolation of this product may allow, for example, drying of the compound obtained; it has been demonstrated that this drying step, whether carried out in an oven or in a mixing dryer, does not modify the crystalline structures obtained at the end of the crystallization process.

By selecting suitable conditions for steps (a) and (b), four different types of product SR 57746 A, namely form I, form II, form III, and a mixture of forms I and III, isolated in step (c), can be determined. characteristics of these types by differential scanning calorimetry (DSC);

3123S / H by means of thermographic records obtained with the PERKIN-ELMER calorimeter under well-defined conditions is obtained by:

- transition temperature between two solid phases; and

- enthalpy value associated with this transition.

Differential Scanning Calorimetry was performed using a PERKIN-ELMER DSC7 device calibrated relative to the endotherms of indium or lead melting and cyclohexane. This analysis was performed using 3 to 6 milligrams of product, which was placed in an aluminum crucible equipped with a corrugated and perforated lid, in a temperature range ranging from 50 ° C to 180 ° C and at a heating rate of 10 ° C / minute using nitrogen as a purge gas.

The transition temperature between the two solid phases and the transition enthalpy value are essential characteristics that are sufficient to identify each crystalline form or a mixture of two of these forms.

These forms can also be characterized by powder X-ray diffractometry. X-ray diffraction profile (Bragg diffraction angles 2 Θ) is obtained with a diffractometer SIEMENS 500 TT equipped with a 40 kV generator, rear monochromator, Cu source of x 1 and silicon holder, wherein the profile of a scanning range of 4 ^{0-40 0} at a rate of 1 7 minutes.

In one preferred embodiment of the invention, step (a) is carried out by heating SR 57746 A at reflux temperature in an ethanol / hydrochloric acid mixture in which the constituents are in the range of 95/5 to 70/30, wherein said heating at reflux temperature is carried out until dissolution is complete and step (b) is carried out by cooling the resulting solution to about 4 ° C at a temperature gradient ranging from 3 ° C / hour to 100 ° C / hour without stirring. Within this convenient

31238 / H of the embodiment in step (c) is an isolated crystalline form of SR 57746 A, hereinafter referred to as Form I, characterized in that it has:

- the transition temperature between two solid phases is 148,4 ° C ± 1,6 ° C; and

- an enthalpy value of this transition of 26,4 J / g ± 1,1 J / g.

Form I of SR 57746 A, which exhibits the above characteristics, represents a further aspect of the invention.

This new crystalline form was also analyzed by the powder X-ray diffraction technique. A qualitative study of the diffraction matrices made it possible to determine that Form I exhibited characteristic lines (2 Θ) at:

-9.9 ° ± 0.3 °

- 14.8 ° ± 0.3 °

-20.8 ° ± 0.3 ° (intensity 100).

Form I is also obtained while the solution in step (b) is cooled by being allowed to stand for a time ranging from 8 to 15 hours and at a temperature ranging from 0 ° C to 5 ° C, this cooling is also carried out without stirring.

In another preferred embodiment of the invention, step (a) is carried out by heating SR 57746 A at reflux temperature in absolute ethanol or in ethyl acetate / water, wherein the constituents are in the range of 95/5 to 75/15, wherein the reflux temperature is maintained until the dissolution is complete, wherein the concentration of the product SR 57746 A in the ethyl acetate / water mixture is in the range of 10 grams / liter to 80 grams / liter and preferably 70 grams / liter, while the concentration of this product in absolute ethanol ranges from 5 grams / liter to 150 grams / liter.

In this preferred embodiment, step (b) is performed by cooling from the reflux temperature to about 5 ° C at a temperature gradient ranging

31238 / H in the range of 100 ° C / hour to 30 ° C / hour and at a stirring rate ranging from 100 rpm to 600 rpm.

Thus, in step (c), another crystalline form, which is hereinafter referred to as Form II, is isolated and is characterized by having:

- a solid-phase transition temperature of 153,9 ° C ± 1,1 ° C; and

- an enthalpy value of this transition of 24,1 J / g ± 1,0 J / g.

Form II of product SR 57746 A, which exhibits the above characteristics, represents a further aspect of the invention.

This new crystalline form was also analyzed by the powder X-ray diffraction technique. A qualitative study of diffraction matrices made it possible to determine that Form II exhibited characteristic lines (2 Θ) at:

-14.5 ° ± 0.3 ⁰ (intensity 100)

-19.3 ° ± 0.3 °

-20.4 ° ± 0.3 °

In another preferred embodiment, step (a) is carried out by heating SR 57746 A at reflux temperature in dimethylsulfoxide until the dissolution is complete and step (b) is performed by cooling the resulting solution to a temperature gradient moving in the range of 3 ° C / hour to 100 ° C / hour and at a stirring rate ranging from 0 rpm to 600 rpm.

The further crystalline form is then isolated in step (c), hereinafter referred to as Form III, which is characterized in that it exhibits:

a transition temperature between two solid phases of 141 ° C ± 2 ° C; and

- an enthalpy value of this transition of 17,6 J / g ± 0,5 J / g.

Form III of SR 57746 A, which exhibits the above characteristics, represents a further aspect of the invention.

31238 / H

In one particularly preferred embodiment, step (a) is carried out by heating SR 57746 A in an ethanol / water mixture in which the constituents are in the range of 95/5 to 70/30, preferably in the range of 90/10 to 85 / 15, wherein the heating is carried out until the dissolution is complete and step (b) is carried out by cooling at a temperature gradient ranging from 5 ° C / hour to 30 ° C / hour, where preferably cooling to 5 ° C at a temperature gradient ranging from 10 ° C / hour to 20 ° C / hour, preferably at a gradient of 10 ° C / hour, and at a stirring rate of 0 rpm / minute to 600 rpm, preferably from 200 rpm to 400 rpm, in a particularly preferred embodiment the mixing speed is 400 rpm Utu.

It has now unexpectedly been found that in step (c) it is possible to reproducibly isolate a mixture of Form I and Form III, as confirmed by differential scanning calorimetry, where the weight ratios of the components range from 80/20 to 60/40, preferably embodiments in the range of 70/30 to 65/35, in a particularly preferred embodiment the ratio is about 66/34.

This mixture consists of particles having a diameter of less than 150 microns.

Forms I, II and III of SR 57746 A and the mixture of Form I and Form III can be micronized to form a pharmaceutical active substance having a particle size of less than 50 microns, preferably less than 30 microns, preferably In embodiments, at least 80% of the particles have a size of less than 10 microns.

This micronization can be carried out in a conventional microcrystal recovery apparatus less than 50 microns in size, such as an ALPINE 200 AS micronizer where SR 57746 A is fed into a micronization chamber (200 millimeter diameter) at a speed in the range of from 15 kg / hour to 50 kg / hour and at work

31238 / H pressure ranging from 1 bar (100,000 Pa) to 6.5 bar (650,000 Pa) where the product obtained is separated by means of a filter bag.

Micronized crystalline Forms I, II and III of SR 57746 A and micronized mixtures of Form I and Form III, wherein the proportion of components is in the range of 80/20 to 60/40, preferably in the range of 70/30 to 65 And in a particularly preferred embodiment, the ratio is about 66/34, being a particularly preferred aspect of the invention.

The availability of well-defined forms of product SR 57746 A or of fixed mixtures of Form I and Form III of this product allows the preparation of pharmaceutical compositions having a constant and reproducible composition.

Furthermore, the preparation of a product having a fine particle size, such as that carried out by micronization, allows, with a view to constant activity, to significantly reduce the effective dosages required to achieve the same therapeutic effect.

Furthermore, it has been demonstrated that the microcrystalline form not only allows the dosage amounts present in the pharmaceutical compositions to be reduced, but in particular also enables uniformity in the oral route of administration and thus achieves a constant therapeutic effect for each patient, whether applied on empty stomach or with food .

The in vitro absorption study of SR 57746 A as a micronized mixture of Form I and Form III was conducted using a 2 monolayer CACO model. This test, which is widely used as a predictive intestinal epithelial model to describe the absorption of pharmaceuticals (see: Artusson, Crit. Rev. Ther. Drug, 1991, 8: 305-330), has shown significant differences in dissolution and permeability between SR 57746 A in the form of a micronized mixture of Form I and Form III by SR 57746 A prepared according to EP 0 101 381.

31238

The results obtained show that in the medium used (Hanks solution supplemented with 10% fetal calf serum and taurocholic acid), dissolution and permeability rates are markedly different for SR 57746 A in the form of a micronized mixture of Form I and Form III and SR 57746 A, was obtained according to EP 0 101 381. Furthermore, it was demonstrated that dissolution and permeability are normalized after micronization, i.e. maintained at a uniform level.

Accordingly, a further aspect of the invention relates to a pharmaceutical composition comprising 1- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) 1,2,3,6-tetrahydropyridine hydrochloride as an active ingredient, in a crystalline form which may optionally be micronized and which is selected from the group consisting of Form I, Form II and Form III, as defined above, and mixtures of Form I and Form III, wherein the component ratios range from 80/20 to 60/40, preferably from 70/30 to 65 / 35, wherein in a particularly preferred embodiment the ratio is 66/34.

The crystalline forms in an embodiment of the invention may be administered by oral, parenteral, sublingual or transdermal routes. The amount of active agent to be administered depends on the nature and severity of the diseases to be treated and the body weight of the patients. Notwithstanding this, the amount of active ingredient present in a unit dose may contain up to 10 milligrams (calculated as the free base) for the non-micronized product, while it may range from 0.1 milligram to 5 milligrams, preferably embodiments in the range of 0.5 milligram to 3 milligrams, in a particularly preferred embodiment, the amount may be 2 milligrams (calculated as the free base). In a preferred embodiment, these unit doses generally comprise 0.5 milligram, 1 milligram, 1.5 milligram, 2 milligrams, 2.5 milligrams or 3 milligrams (calculated as the free base) of the micronized product.

These unit doses will generally be administered one or more times a day, for example one or two times a day, with the total dose in the human body being within the range of a non-micronized product.

3123S -Ή

0.5 milligrams / day to 20 milligrams / day, preferably from 1 milligrams / day to 10 milligrams / day (calculated as the free base), whereas in the case of a micronized product, this dose can range from 0, 2 milligrams / day to 10 milligrams / day, preferably from 1 milligrams / day to 6 milligrams / day (calculated as the free base).

In unit forms of pharmaceutical compositions of the embodiment of the invention, the active ingredient may be administered to animals and humans, preferably the active ingredient is admixed with conventional pharmaceutical carriers for the treatment of the diseases identified in particular in U.S. Pat. 5,026,716, 5,109,005, 5,270,320, 5,292,745 and 5,378,709, and in particular for the treatment of neurodegenerative disorders, in particular amyotrophic lateral sclerosis. Suitable unit dosage forms are those for oral administration, such as tablets, which may be separable, gelatin capsules, powdered forms and granules, and sublingual and buccal forms, and transdermal forms of administration may also be prepared using these new crystalline forms.

In preparing a solid composition in the form of a tablet, the active ingredient is admixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, acacia or the like. These tablets may be coated with sucrose or other suitable substances, or otherwise formulated to provide sustained or delayed activity and thereby provide a sustained release of a predetermined amount of active ingredient.

A gelatin capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

The active ingredient may also be incorporated in the form of microcapsules, which may optionally contain one or more carriers or excipients.

31238 / H

In pharmaceutical compositions according to an embodiment of the invention, the active ingredient may also be present in the form of an inclusive complex in cyclodextrins, ethers or esters thereof.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described by way of specific examples, which are provided by way of illustration only and are not intended to limit the scope of the invention in any way.

Example 1

Mixture containing 19.5 grams of crude 1- (2- (2-naphthyl) ethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, 95 ml absolute ethanol and 4,65 ml 37% acid hydrochloric acid was heated to reflux while stirring until dissolution was complete and then allowed to cool while stirring. At the time when the first crystals began to form (at about 63 ° C), the stirrer was stopped and the reaction mixture stopped. The mixture was kept at 0 ° C to 5 ° C overnight After filtration, the product was twice pasted in 30 ml of absolute ethanol and then dried overnight in vacuo at 40 ° C.

Under these conditions, 12.8 g of Form I of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride (SR 57746 A, Form I) were obtained.

Using the differential scanning calorimetry technique, it was found that the product SR 57746 A, Form I exhibits:

a transition temperature between two solid phases of 148 ° C to 149 ° C; and

the enthalpy value of this transition is 26.4 J / g.

A corresponding thermogram is shown in FIG. First

31238 / H

When analyzed by the X-ray powder diffraction technique on a SIEMENS 500 TT type apparatus under the conditions described above, the product SR 57746 A, Form I obtained by this method of preparation showed characteristic lines (Bragg angles 2 Θ) at 9.8 °, 14.7 ⁰ and 20.7 ° (relative intensity 100).

The profile obtained by the X-ray powder diffraction technique (diffraction angles) in the analysis of SR 57746 A, Form I obtained in this preparation is given by the significant lines which, together with the relative intensity expressed as a percentage of the most intense line, are shown in Table 1.

TABLE 1

SR 57746 A - form I

Diffraction bands (Bragg angles 2 Θ) Relative intensity 9,798 23.44 14,758 79,68 15,174 45,73 16,584 49,31 16,922 34.30 17,458 35.91 17,814 21.48 18,403 32.33 20,741 100.00 21,367 29.91 22,310 28.98 24,482 22.75 24,768 67.67 25,644 40.18 28,803 39.03

31238 / H

Example 2

In a METTLER RC1-type calorimetric reactor equipped with an 8 cm high speed stirrer, a mixture containing 70 grams of crude 1- [2 (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) - was heated to reflux. 1,2,3,6 tetrahydropyridine hydrochloride and 1 liter of absolute ethanol, and refluxing until complete dissolution of the product. The resulting solution was cooled to 10 ° C at a cooling rate of 80 ° C / hour and a stirring speed of 500 rpm. The resulting precipitated product was filtered off and dried overnight under vacuum at 45 ° C.

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) was obtained.

Using the differential scanning calorimetry technique, it was found that the product SR 57746 A, Form II exhibits:

- a solid-phase transition temperature of 153 ° C to 155 ° C; and

- an enthalpy value of this transition of 24.1 J / g.

A corresponding thermogram is shown in FIG. Second

When analyzed by the X-ray powder diffraction technique on a SIEMENS 500 TT type apparatus under the conditions described above, SR 57746 A, Form II obtained by this preparation method showed characteristic lines (Bragg angles of 2 Θ) at 14.3 ° (relative intensity) 100), 19.2 ° and 20.5

The profile obtained by the X-ray powder diffraction technique (diffraction angles) in the analysis of SR 57746 A, Form II obtained in this preparation is given by the significant lines which, together with the relative intensity expressed as a percentage of the most intense line, are shown in Table 2.

31238 / H

TABLE 2

SR 57746 A - form II

Diffraction bands (Bragg angles 2 Θ) Relative intensity 14,348 100.00 16,300 21.68 16,748 57.51 17,209 68.98 19,173 34.10 20,147 37.38 20,493 28.52 20,832 33.62 24,332 37.28 24,902 24.57 25,237 41.71 25,817 24.57

Example 3

A mixture of 2 grams of crude 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride and 50 ml of dimethylsulfoxide was heated to reflux until it was refluxed. dissolution was complete, then the mixture was allowed to cool overnight, and the crystalline product formed was then separated and dried at 45 ° C.

Under these conditions, Form III of 1- [2- (2-naphthyl) ethyl] -4 (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride (SR 57746 A, Form III) was obtained.

31238 / H

Using the differential scanning calorimetry technique, it was found that the product SR 57746 A, Form III exhibits:

a transition temperature between two solid phases of 141 ° C to 142 ° C; and

the enthalpy value of this transition is 17.6 J / g.

A corresponding thermogram is shown in FIG. Third

Example 4

The mixture containing 100 grams of crude 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride and 1 liter of ethanol / water with a 90/10 ratio The mixture was stirred at reflux until the dissolution of the product was complete. The resulting solution was cooled from reflux to 5 ° C, with stirring using a high speed stirrer operating at 400 rpm and at a cooling rate of 10 ° C / minute. The resulting crystalline product was then filtered off and dried overnight under vacuum at rt. temperature 45 ° C.

Under these conditions, 1- (2- (2-naphthyl) ethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride was obtained as a mixture of Form I and Form III at a component ratio of 65.7 / 34, 3 (SR 57746 A, Form I / III).

Using the differential scanning calorimetry technique, it was found that the product SR 57746 A, Form I / III exhibited the thermogram shown in FIG. 4, which contains only two characteristic peaks corresponding to Form I and Form III.

Examples 5 and 6

In these examples, the procedure described in Example 2 was used, using the following cooling rates and mixing rates in two different preparations:

cooling at 100 ° C / hour and stirring at 600 rpm (Example 5);

31238 / H

cooling at 30 ° C / hour and stirring at 300 rpm (Example 6).

Under these conditions, product SR 57746 A, Form II was obtained.

Thus, it was found that when working in absolute ethanol at a concentration of 70 grams / liter, the production of Form II depends on the cooling rate and the mixing rate in accordance with a linear equation of the type y = ax + b.

To obtain Form II under these conditions, this equation has the following form:

R _max = 4.23.V + 170.51 where R _max represents the stirring speed in rpm and V represents the cooling rate in ° C / hour. Consequently, to obtain form II, the stirrer speed must be given at a cooling rate less than the rate of R _max or equal to the rate of R _max.

Example 7

The mixture containing 15 grams of crude 1- (2- (2-naphthyl) ethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride and 1 liter of ethyl acetate / water with a 90/10 ratio The reaction solution was cooled to 5 ° C, at a cooling rate of 60 ° C / minute and with stirring at a rate of 60 ° C / minute. 150 rpm, and then the resulting precipitated product was filtered off and dried under vacuum to give SR 57746 A, Form II, which was identical to the product obtained according to Example 2.

Examples 8 to 11

In four different types of preparation, crude 1- (2- (2-naphthyl) ethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride was at a concentration of 70 grams / liter in ethyl acetate / water with component ratio 92/8 (reaction volume 1.3 liters) heated to reflux in

31238 / H reactor type RC 1, which was connected to a particle monitoring device of type PARTEC® 100 from LASANTEC and equipped with a high-speed stirrer with a diameter of 8 centimeters. After complete dissolution, the solution was under the following conditions:

cooling at 100 ° C / hour and stirring at 400 rpm (Example 8);

cooling at 80 ° C / hour and stirring at 300 rpm (Example 9);

cooling at 50 ° C / hour and stirring at 200 rpm (Example 10);

cooling at 30 ° C / hour and stirring at 100 rpm (Example 11).

Under these conditions, product SR 57746 A, Form II was obtained.

Thus, it was found that when working in an ethyl acetate / water mixture with a 92/8 component ratio and a concentration of 70 grams / liter, the production of Form II depends on the cooling rate and the mixing rate in accordance with the following linear equation:

Rmax = 4.14.V - 18,9 where R _max represents the stirring speed in rpm and V represents the cooling rate in ° C / hour.

Thus, if Form II is to be obtained, the stirring speed must be less than or equal to R _max at a given cooling rate.

Example 12

Crude 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6 tetrahydropyridine hydrochloride was at a concentration of 60.6 grams / liter in a 90/10 acetone / water mixture heated to reflux while stirring until dissolution

31238, úplné product complete. Subsequently, the procedure described in Example 4 was followed to obtain SR 57746 A, a mixed form I / III with a component ratio of 80/20.

Example 13

Crude 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6 tetrahydropyridine hydrochloride at a concentration of 100 g / liter was heated to reflux while stirring in methanol for so long. until the dissolution was complete. Subsequently, the procedure described in Example 4 was followed to obtain SR 57746 A, a mixed form I / III with a component ratio of 80/20 which was identical to the product obtained in Example 12.

Example 14

Crude 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6 tetrahydropyridine hydrochloride was heated at a concentration of 100 grams / liter in a 70/30 ethanol / water mixture at at reflux while stirring until dissolution was complete. Subsequently, the procedure described in Example 4 was followed to obtain SR 57746 A, a mixed form I / III with a component ratio of 65.7 / 34.3 which was identical to the product obtained in Example 4.

Example 15 kg of SR 57746 A, Mixed Form I / III described in Example 4, were fed into a micronization chamber (200 milliliters diameter) of the ALPINE 200 AS micronizer at a rate of 25 kilograms / hour and at a working pressure of 6.5 bar. ) and the micronized product was collected using a filter bag. In this way, micronized product SR 57746 A, a mixed form I / III with a particle size distribution, was obtained in which all particles had a size of less than 20 microns and 85% of the particles had a size of less than 10 microns.

31238 / H

Analysis of the resulting product by differential scanning calorimetry showed that transition temperatures were not affected by micronization. These transitions were solid-solid transitions. Prior to melting, which began at 250 ° C, the product SR 57746 A was subject to degradation. and

Example 16

Pharmaceutical composition containing as active ingredient a micronized product SR 577 46 A, a mixed form I / III obtained according to Example 15 described above:

active substance 2,192 mg maize starch 141,218 mg anhydrous colloidal silica 0.200 mg magnesium stearate 0.400 mg

The active ingredient was screened at 0.2 mm and then mixed with the carrier material. The mixture thus formed was screened at 0.315 mm, mixed again and then screened at 0.315. Following the final mixing, the composition was fed to No. 3 gelatin capsules in an amount of 170 milligrams of the composition containing an amount of micronized product SR 57746 A, a mixed form I / III corresponding to 2 milligrams of 1- [2- (2-naphthyl) ethyl] - Of 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine base.

Claims (25)

PATENT CLAIMS Process for crystallizing 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride (SR 57746 A), characterized in that (a) the compound is heating to dissolve in a solvent selected from the group consisting of from one to three carbon atoms, ketones containing from three to six carbon atoms, dimethylsulfoxide and ethyl acetate, which solvent may optionally contain water or an aqueous solution of hydrochloric acid in an amount from 5% to 30%; (b) cooling the resulting solution to -10 ° C / + 10 ° C at a rate ranging from 3 ° C / hour to 100 ° C / hour while stirring at a rate of 0 ° C / hour rpm to 600 rpm; and (c) recovering the resulting product and optionally also micronizing. The process according to claim 1, wherein step (a) is carried out by heating SR 57746 A at reflux temperature in an ethanol / hydrochloric acid mixture in which the constituents are in the range of 95/5 to 70 / 30, wherein the refluxing is carried out until dissolution is complete, step (b) is performed by cooling the resulting solution to about 4 ° C at a temperature gradient ranging from 3 ° C / hour to 100 ° C / hour and without stirring, and in step (c), Form I of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride is then isolated . The process according to claim 1, wherein step (a) is performed by heating SR 57746 A at reflux temperature. 3123S H condenser in absolute ethanol or in ethyl acetate / water, where the constituents are in the range of 95/5 to 75/15, where the reflux is continued until dissolution is complete, wherein the concentration of this product in the ethyl acetate / water solution ranges from 10 grams / liter to 80 grams / liter, while the concentration of this product in absolute ethanol ranges from 5 grams / liter to 150 grams / liter, step (b) is effected by cooling from reflux to about 5 ° C in a temperature gradient ranging from 100 ° C / hour to 30 ° C / hour at a stirring rate ranging from 100 rpm to 600 rpm. 1 - [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6 tetrahydropyridine hydrochloride is isolated in step (c). The process of claim 1, wherein step (a) is carried out by heating SR 57746 A at reflux temperature in dimethylsulfoxide, wherein the heating at reflux temperature is continued until dissolution is complete, step (a). b) is effected by cooling the resulting solution to a temperature gradient ranging from 3 ° C / hour to 100 ° C / hour at a stirring rate ranging from 0 rpm to 600 rpm and within step (c) is: then isolated Form III of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride. The process of claim 1, wherein step (a) is carried out by heating SR 57746 A at reflux temperature in an ethanol / water mixture wherein the constituents are in the range of 95/5 to 70/30 wherein the heating at boiling temperature is carried out until dissolution is complete, step (b) is carried out by cooling the resulting solution at a temperature gradient ranging from 5 ° C / hour to 30 ° C / hour at a stirring rate of in the range of 0 rpm to 600 rpm, and in step (c), the isolated form of the mixed form I / III 1 - [2 31238 H - (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6 tetrahydropyridine hydrochloride, wherein the component ratio ranges from 80/20 to 60/40. Method according to claim 5, characterized in that step (a) is an ethanol / water mixture in which the constituents give 90/10, step (b) is carried out by cooling the resulting solution to 5 ° C at a temperature gradient moving in the range of 10 ° C / hour to 20 ° C / hour and at a stirring speed ranging from 200 rpm to 400 rpm and in step (c), Form I / III 1- [2 - (2 naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6 tetrahydropyridine hydrochloride, wherein the component ratio ranges from 70/30 to 65/35. Method according to claim 6, characterized in that in step (b) the temperature gradient gives 10 ° C / hour and the stirring speed is 200 rpm and in step (c) the form I / III 1- [2] is then isolated. - (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride having a component ratio of 66/34. Method according to one of Claims 1 to 7, characterized in that a paddle stirrer is used. 9. Form I 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetrahydropyridine hydrochloride obtainable by the process of claim 2. 10. Form II 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetrahydropyridine hydrochloride obtainable by the process of claim 3. 11. Form I 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetrahydropyridine hydrochloride obtainable by the process of claim 4. A mixture of Form I and Form III of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride obtainable by the process of one of claims 5 to 7. 31238Ή 13. Form I 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetrahydropyridine hydrochloride characterized by: - the transition temperature between two solid phases is 148,4 ° C ± 1,6 ° C; and - an enthalpy value of this transition of 26,4 J / g ± 1,1 J / g. Form I according to claim 13, characterized in that its analysis by powder X-ray diffraction technique shows characteristic lines (Bragg angles 2 Θ) at: - 9.9 ° ± 0.3 ° - 14.8 ° ± 0.3 ° -20.8 ° ± 0.3 ° (intensity 100). 15. Form II 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetrahydropyridine hydrochloride characterized by: - a solid-phase transition temperature of 153,9 ° C ± 1,1 ° C; and - an enthalpy value of this transition of 24,1 J / g ± 1,0 J / g. Form II according to claim 15, characterized in that its analysis by powder X-ray diffraction technique shows characteristic lines (Bragg angles 2 Θ) at: -14.5 ° ± 0.3 ° (intensity 100) - 19.3 ° ± 0.3 ° -20.4 ° ± 0.3 ° 17. Form III 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetrahydropyridine hydrochloride characterized by: a transition temperature between two solid phases of 141 ° C ± 2 ° C; and - an enthalpy value of this transition of 17,6 J / g ± 0,5 J / g. A crystalline form according to any one of claims 9 to 17, characterized in that it is in a micronized state. 31238 / H A mixture of Form I according to claim 13 or 14 and Form III according to claim 17, characterized in that the proportion of Form I to Form III is in the range of 80/20 to 60/40. 20. The composition of claim 19 wherein the proportion of Form I to Form III is in the range of 70/30 to 65/35. 21. The composition of claim 20 wherein the proportion of Form I to Form III is 66/34. Composition according to one of claims 19 to 21, characterized in that it is in a micronized state. 23. A pharmaceutical composition comprising as active ingredient 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6 tetrahydropyridine hydrochloride in crystalline form, which may be optionally micronized and which is selected from the group consisting of Form I, Form II and Form III, and a mixture of Form I and Form III according to one of claims 9 to 21. 24. The composition of claim 23, wherein the active ingredient is a unit dose of the composition of claim 22. The composition of claim 24, wherein each unit dose comprises an amount of micronized active ingredient that corresponds to a dose selected from 0.5 milligrams, 1 milligrams, 1.5 milligrams, 2 milligrams, 2.5 milligrams, or 3 milligrams. calculated as the free base).