SK285088B6 - Method for crystallizing of 1-[2-(naphth-2-yl)ethyl]-4-(3- trifluoromethylphenyl)-1,2,3,6-tetra-hydropyridine hydrochloride, mixture of form I and form III of 1-[2-(naphth-2-yl)ethyl]-4-(3- trifluoromethylphenyl)-1,2,3,6-tetra-hydropyridine hydrochloride and pharmaceutical composition containing its - Google Patents

Abstract

Method of crystallizing 1-[2-(naphth-2-yl)ethyl]-4-(3- trifluoromethylphenyl)-1,2,3,6-tetra-hydropyridine hydrochloride, characterized in that: a) 1-[2-(naphth-2-yl)ethyl]-4-(3- trifluoromethylphenyl)-1,2,3,6-tetra-hydropyridine hydrochloride is heated by refluxing in a ratio of 95/5 to 70/30 ethanol/water mixture until dissolution is complete; b) the resulting solution is cooled to temperature -10/+10 °C with a temperature gradient of 5 to 30 °C per hour and a stirrer speed at the rate from 0 to 600 rpm; and c) a form I/form III mixture of 1-[2-(naphth-2- yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetra-hydropyridine hydrochloride in a ratio of 80/20 to 60/40 is isolated and optionally micronized below 50 micrometers. Mixture of form I and form III 1-[2-(naphth-2-yl)ethyl]-4-(3-trifluoromethylphenyl)- 1,2,3,6-tetra-hydropyridine hydrochloride and a pharmaceutical composition comprising this crystalline mixture of form I/form III.

Description

Technical field

The present invention relates to a process for the crystallization of 1- [2- (naphth-2-yl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, a mixture of Forms I and III thereof, and a pharmaceutical composition. containing this substance, in particular in the form of a crystalline Form I / Form III mixture as the active substance.

BACKGROUND OF THE INVENTION

1- [2- (2-Naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, hereinafter referred to as SR 57746, and its pharmaceutically acceptable salts were first described in European patent no. 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).

European patent 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.

In preclinical tests, especially in animal pharmacological and toxicological tests, SR 57746 A had 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 in 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 (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 the product SR 57746 A is obtained, which consists of crystals whose size is not constant and exceeds 150 micrometers, 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 has been found that the ratios of these different forms do not reach constant values in different batches of SR 57746 A, which complicates the control of the characteristics of the starting material for the manufacture of pharmaceutical compositions.

SUMMARY OF THE INVENTION

In the context of the present invention, it is also important to emphasize that the three forms described are not isolated and appear in this prior art product (see EP 0 101 381) as an integral part of the product. In other words, the prior art process results in a product that is not a single chemical individual but a mixture of several forms. It follows that the compound of this document is not a pure product, as previously known, but a mixture of three crystalline forms, but this product does not have the same characteristics as the isolated forms of the present invention.

The process of crystallizing 1- [2- (na-2-yl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride according to the present invention comprises the steps of:

(a) refluxing 1- [2- (naphth-2-yl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride in ethanol / water (95/5 to 70) 30 until the dissolution is complete,

(b) cooling the resulting solution to a boiling point ranging from -10 ° C to + 10 ° C using a temperature gradient of 5 to 30 ° C per hour and a stirring speed of 0 to 600 rpm; and

c) isolating the form I / form III of 1- [2- (naphth-2-yl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, wherein the ratio of the components is in the range of 80/20 to 60/40 and optionally reducing the particles of this mixture by 50 µm.

In a preferred embodiment of the process according to the invention, ethanol / water is used in step (a) in which the constituents are 90/10, step (b) is carried out by cooling the resulting solution to 5 ° C at a temperature gradient ranging from 10 ° C / hour to 20 ° C / hour and at a stirring speed ranging from 200 rpm to 400 rpm and in step (c) the Form 1 / Form III hydrochloride [2- ( naphth-2-yl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, wherein the component ratio ranges from 70/30 to 65/35. Preferably, in step (b) the temperature gradient is 10 ° C / hour and the stirring speed is 400 rpm, and in step (c) the Form I / Form III hydrochloride mixture 1- [2- (naphth-2-yl) is isolated (ethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, in which the component ratio is 66/34. In carrying out this process, the paddle mixer is preferably used.

The present invention also relates to a mixture of Form I and Form III of 1- [2- (naphth-2-yl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride. that the ratio of Form I / Form III ranges from 80/20 to 60/40, wherein Form I has:

a solid - solid transition temperature of 148,4 ° C ± 1,6 ° C, and

an enthalpy value of this transition of 26,4 J / g +1,1 J / g, and

- the X-ray powder diffraction pattern has characteristic lines (Bragg angles 2 Θ) at:

-9.9 ° ± 0.3 °

- 14.8 ° + 0.3 °

-20.8 ° ± 0.3 ° (intensity 100);

and Form III has:

a solid - solid transition temperature of 141 ° C ± 2 ° C, and

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

Preferred is a composition in which the Form I / Form III ratio is in the range of 70/30 to 65/35, and more preferably the composition in which the Form I / Form III ratio is 66/34. Also preferred is a composition in which the particle size of the composition is less than 50 µm.

The present invention also provides a pharmaceutical composition comprising 1- [2- (naphth-2-yl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3 as its active ingredient. 6-tetrahydropyridine in the form of any of said crystalline form I / form III.

Preferred is a pharmaceutical composition in unit dosage form wherein the particle size of the Form I / Form III mixture is less than 50 µm. Preferably, each unit dose contains an amount of micronized active agent that corresponds to a dose selected from 0.5 milligram, 1.5 milligram, 2 milligrams, 2.5 milligrams or 3 milligrams, calculated as the free base.

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 the pharmacokinetic and pharmacodynamic characteristics, the ability to control the reproducibility of the SR 57746 A composition in crystalline form is very beneficial for the marketing of pharmaceutical products.

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.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings show thermographic records obtained using differential scanning calorimetry techniques for analyzing Form I, Form II, Form III, and a Form I / Form III mixture in 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 the transition temperature between two solid phases ranging from 148 ° C to 149 ° C.

In FIG. 2 shows a thermographic recording of Form II of SR 57746 A, prepared according to Example 2, wherein the thermographic recording was obtained by differential scanning calorimetry in the temperature range from 50 ° C to 180 ° C. This thermographic record shows a 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 a temperature range of 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 recording of a mixture of Form I and Form III prepared according to Example 4, wherein the thermographic recording was obtained by differential scanning calorimetry in the temperature range from 50 ° C to 180 ° C. This thermographic record shows the solid phase-solid phase transition temperatures for two different forms.

In contrast to the prior art (see EP 101381), Form I, Form II, Form II, and Form I / Form III of the present invention have thermograms that are quite different from the thermogram mentioned for SR 57746 A according to the prior art. technique.

Thus, in fact, the compound of document D1 is different from the crystalline forms obtained by the process of the present invention, both structurally and in terms of pharmacological activity.

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, wherein the heating may optionally be carried out in the presence of water, preferably at reflux.

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, in a concentration ranging from 15 grams / liter to 150 grams / liter), whereas acetone, methyl ethyl ketone, isopropanol or ethyl acetate does not completely dissolve the product 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 so as to avoid excessive dissolution and thus 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 expressed 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 100/0 to 70/30 100/0 to 70/30, acetone / water: constituents ranging from 95/5 to 70/30, methyl ethyl ketone / water: constituents ranging from 95/5 to 80/20, ethyl acetate / water: the proportion of components ranging from 95/5 to 70/30 and dimethylsulfoxide.

As mentioned, 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, from 150 grams / liter to 300 grams / liter for ethanol and ethanol / water mixtures.

The product SR 577 46 A is preferably dissolved so that its concentration in ethanol, in a 90/10 ethanol / water mixture or in methanol is in the range of 5 grams / liter to 150 grams / liter, preferably in the range from 100 grams / liter to 150 grams / liter, or that its concentration in the 90/10 acetone / water mixture gives about 60 grams / liter, or that its concentration in the 95/15 methyl ethyl ketone / water mixture is in the range of from 100 grams / liter to 125 grams / liter, or so that its concentration in the 90/10 ethyl acetate / water mixture gives 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, optionally 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 in the range of 4/5 to 2/5 of the diameter of the reactor 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 two forms in fixed proportions, depends on the simultaneous action of the 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 obtained in this way is isolated by conventional techniques and optionally also micronized.

Isolation of this product may allow, for example, drying of the obtained compound, and it has been shown 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 product types of SR 57746 A, namely Form I, Form II, Form III, and a mixture of Form I and III can be isolated in step (c), whereby the essential characteristics can be determined. of these types by differential scanning calorimetry (DSC); by thermographic recordings obtained using a PERKIN-ELMER calorimeter under well-defined conditions, the following are obtained:

the temperature of transition 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 india 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. The X-ray diffraction pattern (2 B Bragg diffraction angles) was obtained using a SIEMENS 500 TT diffractometer equipped with a 40 kV generator, a rear monochromator, a Cu kx 1 source and a silicon mount, scanned from 4 ° to 40 ° at 1 "/ minute.

In a preferred embodiment of the invention, step (a) is carried out by heating SR 57746 A at reflux temperature in an ethanol / hydrochloric acid mixture, wherein the constituents are in the range of 95/5 to 70/30, heating to reflux is continued 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 and without stirring. In this preferred embodiment, the crystalline form of SR 57746 A, which is hereinafter referred to as Form I, is isolated in step (c) and is characterized in that it has:

temperature between two solid phases of 148,4 ° C ± 1,6 ° C, and

the enthalpy value of this transition is 26.4 J / g + 1.1 J / g.

Form I of SR 57746 A having the above characteristics was also analyzed by powder X-ray diffraction technique. A qualitative study of diffraction matrices made it possible to determine that Form I has characteristic lines (20) 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 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 from 100 ° C / hour to 30 ° C / hour and at a stirring rate ranging from 100 rpm. / minute 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:

- transition temperature between two solid phases 153,9 ° C +1,1 ° Ca

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

Form II of SR 57746 A having the above characteristics was also analyzed by powder X-ray diffraction. A qualitative study of diffraction matrices made it possible to determine that Form II has characteristic lines (2 Θ) at:

-14.5 ° ± 0.3 ° (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" (SR 57746), characterized in that it has:

a temperature of transition 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.

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

It has 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, in a preferred embodiment ranging from 70/30 to 65/35, in a particularly preferred embodiment the ratio being 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 pharmaceutically active agent wherein the particle size is less than 50 microns, preferably less than 30 microns, preferably In an embodiment, at least 80% of the particles are smaller than microns in size.

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 to a micronization chamber (200 millimeter diameter) at a speed in the range from 15 kg / hour to 50 kg / hour and at an operating pressure ranging from 1 bar to 6.5 bar 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 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, makes it possible, in view of the constant activity, to significantly reduce the effective doses necessary to achieve the same therapeutic effect.

Furthermore, it has been demonstrated that the microcrystalline form not only makes it possible to limit the dosages present in the pharmaceutical compositions, but in particular also to achieve uniformity in the oral route of administration, thus achieving a constant therapeutic effect for each patient whether the product is applied to an empty stomach or with food.

The in vitro absorption study of SR 57746 A in the form of a micronized mixture of Form I and Form III was conducted using the CACO model based on 2 monolayers. This test, which is widely used as a predictive intestinal epithelial model to describe the absorption of pharmaceuticals (see P. 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.

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.

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

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 be 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 for the micronized product, preferably 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 per day, for example one or two times per day, wherein the total dose in the human body for the non-micronized product may range from 0.5 milligrams / defl to 20 milligrams / day, preferably in the range of 1 milligram / day to 10 milligrams / day (calculated as the free base), while in the case of a micronized product, this dose can range from 0.2 milligrams / day to 10 milligrams / day, preferably in the range of from 1 milligram / 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 the preparation of a solid composition in the form of tablets, 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.

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% hydrochloric acid was heated to reflux while stirring until dissolution was complete and then allowed to cool with continuous stirring. When the first crystals began to form (at about 63 ° C), the stirrer was stopped and the reaction mixture was maintained at a temperature ranging from 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 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride Form I (SR 57746 A, Form I) were obtained. .

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

a solids transition temperature 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

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

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) hydrochloride was heated to reflux. -1,2,3,6-tetrahydropyridine and 1 liter of absolute ethanol were heated until the product was dissolved. 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, 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride Form II (SR 57746 A, Form II) was obtained.

Using the technique of differential scanning calorimetry it was found that the product SR 57746 A, form II has:

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 device under the above conditions, the product SR 57746 A, Form II, obtained by this method of preparation, had characteristic lines (Bragg angles 2?) 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.

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 dimethyl sulfoxide was heated at reflux for so long. until the dissolution was complete, the mixture was allowed to cool overnight and the crystalline product formed was separated and dried at 45 ° C.

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

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

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

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

A corresponding thermogram is shown in FIG. 3. 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 90/10 ethanol / water was heated to reflux until stirring until the product dissolution 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 in vacuo at 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 1 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 has 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, with the following cooling rates and mixing rates being used in two different preparations:

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

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 _nliix 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 rate must be less than or equal to the rate R ^ at a given cooling rate D ^ 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 90/10 was during stirring using a high-speed stirrer with a diameter of 8 cm, heated to reflux until the dissolution of the product was complete. The resulting solution was cooled to 5 ° C, at a cooling rate of 60 ° C / minute and with stirring at 150 rpm, and then the resulting precipitated product was filtered 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 a component ratio of 92/8 (reaction volume of 1.3 liters) heated to reflux in an RC 1 reactor coupled to a LASANTEC PARTEC® 100 particle monitoring device equipped with a high-speed stirrer with a diameter 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 at a concentration of 70 grams / liter, production of Form II depends on the cooling rate and the mixing rate in accordance with the following linear equation:

R _max = 4.14.V-18.9, where R _nOJ represents the stirring speed in rpm and V represents the cooling rate in ° C / hour.

Thus, if Form II is to be obtained, the agitation rate at a given cooling rate must be less than or equal to R _{max of 1mx} .

Example 12

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

Example 13

The 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. 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 an 80/20 component ratio that was identical to the product obtained in Example 12.

Example 14

The crude 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride was at a concentration of 100 grams / liter in a 70/30 ethanol / water mixture heated to 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 was fed into a micronization chamber (200 milliliters diameter) of the ALPINE 200 AS micronizer at a speed 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 were less than 20 microns in size and 85% of the particles were less than 10 microns in size.

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.

Example 16

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

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 final mixing, the composition was fed to No. 3 gelatin capsules at 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] - 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine base.

Claims (11)

PATENT CLAIMS A process for the crystallization of 1- [2- (naphth-2-yl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, comprising the steps of: (a) refluxing 1- [2- (naphth-2-yl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride in a 95/5 to 70/30 ethanol / water mixture as long as the dissolution is complete, (b) cooling the resulting solution to a temperature in the range of -10 ° C to + 10 ° C using a temperature gradient of 5 to 30 ° C per hour and a stirring rate of 0 to 600 rpm; and c) isolating 1- [2- (naphth-2-yl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride Form I / Form III, wherein the ratio of the components is in the range of 80/20 to 60/40 and optionally reducing the particles of this mixture to below 50 µm. Method according to claim 1, characterized in that in step (a) an ethanol / water mixture is used in which the constituents are 90/10, step (b) is carried out by cooling the resulting solution to 5 ° C in a temperature gradient ranging from 10 ° C / hour to 20 ° C / hour and at a stirring rate ranging from 200 rpm to 400 rpm and in step (c) the Form I / Form III hydrochloride mixture is then isolated 1- [2- (naphth-2-yl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, wherein the component ratio ranges from 70/30 to 65/35. Process according to claim 2, characterized in that in step (b) the temperature gradient is 10 ° C / hour and the stirring speed is 400 rpm and in step (c) the form I / form III hydrochloride mixture is then isolated 1- [2- (naphth-2-yl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, wherein the component ratio is 66/34. Method according to one of claims 1 to 3, characterized in that a paddle stirrer is used. A mixture of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride Form I and Form III, characterized in that the ratio of the form I / Form III ranges from 80/20 to 60/40, with Form I having: solid-solid transition temperature 148.4 ° C +1.6 ° C; and an enthalpy value of this transition of 26,4 J / g ± 1,1 J / g, and - the X-ray powder diffraction pattern has characteristic lines (Bragg angles 2 Θ) at: - 9.9 ° ± 0.3 °, - 14.8 ° + 0.3 °, - 20,8 ° ± 0,3 ° (intensity 100) and Form III has: a solid-solid transition temperature of 141 ° C +2 ° C; and - an enthalpy value of this transition of 17,6 J / g ± 0,5 J / g. A composition according to claim 5, wherein the form I / form III ratio is in the range of 70/30 to 65/35. Composition according to claim 6, characterized in that the ratio of form 1 / form III is 66/34. Composition according to one of claims 5 to 7, characterized in that the particle size in the mixture is less than 50 µm. 9. A pharmaceutical composition comprising as active ingredient 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride in the form of a crystalline mixture Form I / Form III according to any one of claims 5 to 8. A pharmaceutical composition according to claim 9, characterized in that it is in unit dosage form, wherein the particle size in the Form I / Form III mixture is less than 50 µm. Pharmaceutical composition according to claim 10, characterized in that each unit dose contains an amount of micronized active substance corresponding to a dose selected from 0.5 milligram, 1 milligram, 1.5 milligram, 2 milligrams, 2.5 milligrams or 2.5 milligrams or 2.5 milligrams or 2.5 milligrams. 3 milligrams, calculated as the free base.