NO312364B1 - Process for crystallizing a tetrahydropyridine derivative and resulting crystalline forms - Google Patents

Description

The present invention relates to a method for crystallization of a tetrahydropyridine derivative, the new crystalline forms thereby obtained and a pharmaceutical mixture containing said tetrahydropyridine derivative in a given crystalline form, as active ingredient.

The present invention specifically relates to a method for crystallization of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, three crystalline forms of this product, a defined mixture of two of these three forms and a pharmaceutical mixture containing one of the forms or a mixture of two of the forms.

1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, hereinafter referred to by its code number SR 57746, and its pharmaceutically acceptable salts, were first described in EP 0 101 381 as anorexigenic agents and later as anti-anxiety-depressants (US patent 5 026 716), anti-constipation agents (US patent 5 109 005), neurotropic agents (US patent 5 270 320), free radical inhibitors (US Patent 5,292,745) and cardioprotective agents (US Patent 5,378,709).

EP 0 101 381 describes SR 57746 in the form of the hydrochloride, hereinafter referred to as SR 57746 A, and this salt was used in preclinical and clinical trials on healthy subjects. According to this document, SR 57746 A is isolated by crystallization from ethanol, especially absolute ethanol.

In the preclinical trials, especially in pharmacological and toxicological tests on animals, SR 57746 A showed a constant activity and behavior. Likewise, the pharmacokinetic studies on animals produced consistent and reproducible results.

In the clinical trials conducted on healthy subjects (Phase I), however, SR 57746 A was found to exhibit high variability in the plasma concentrations and with regard to the pharmacodynamic effects of the active substance.

In the first clinical trials on patients suffering from very severe diseases, especially amyotrophic lateral sclerosis, the doses of SR 57746 A were kept very low, namely 2 mg/day, a dose where the product showed promise (W.G. Bradley, "New drugs for amyotrophic lateral sclerosis", American Academy of Neurology meeting, March, 23-30, 1996; pages 240-23/240-28).

It has also been shown that the production of larger quantities of SR 57746 A according to the isolation method described in EP 0 101 381 does not produce a product with constant characteristics which make it possible to avoid the disadvantages recorded in Phase I of the clinical trials.

It thus appeared that the SR 57746 A obtained by the isolation method described in EP 0 101 381 consisted of crystals of a size which is not constant and which is greater than 150 micrometres; specifically 150-

600 micrometers for at least approx. 75% of the crystals concerned.

It has also been found that the SR 57746 A which is obtained according to the method described in EP 0 101 381, according to differential scanning calorimetry, consists of at least three different forms.

Finally, it has been shown that the respective ratios between the different forms are not constant in different production rates of SR 57746 A, which makes it difficult to control the characteristics of the starting material for the production of pharmaceutical mixtures.

It has now been shown that by carrying out the crystallization of SR 57746 A under suitable and constant conditions with regard to 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 these three forms in fixed and reproducible conditions.

More specifically, it has been shown that:

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

form II of SR 57746 A is obtained by cooling a solution of SR 57746 A in absolute ethanol or in an ethyl acetate/water mixture under controlled conditions with respect to cooling rate and stirring rate;

form III of SR 57746 A is obtained by cooling a solution of SR 57746 A in dimethyl sulfoxide; and

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

It has also been shown that these new crystalline forms, either as such or in solid mixtures of two of the forms, are absorbed evenly and reproducibly and make it easier to determine the optimal dose of the active substance. Besides the improvement in pharmacokinetics and pharmacodynamics, the ability to control the reproducibility of the mixture of SR 57746 A in crystalline form is very beneficial when it comes to marketing the drug.

Finally, it has been shown that if the new crystalline forms or mixtures of two of the aforementioned forms consist of very small crystals, especially micronized crystals, the activity of the active substance increases significantly, and the absorption of this is uniform and constant, thus making it possible to administer small doses with a very good therapeutic response and at the same time control any side effects.

The accompanying figures show thermograms obtained by subjecting Form I, Form II, Form III and Form I/Form III mixture in a ratio of 65.7/34.3 to differential scanning calorimetry. Figure 1 shows the thermogram of form I of SR 57746 A, prepared according to Example 1, the thermogram obtained by differential scanning calorimetry at 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, the thermogram obtained by differential scanning calorimetry at 50°C to 180°C. This thermogram shows a solid/solid transition temperature of 153-155°C. Figure 3 shows the thermogram of form III of SR 57746 A, prepared according to Example 3, where the thermogram was obtained by differential scanning calorimetry at 50°C to 180°C. This thermogram shows a solid/solid transition temperature of 141-142°C. Figure 4 shows the thermogram of a Form I/Form III mixture, prepared according to Example 4, the thermogram obtained by differential scanning calorimetry at 50°C to 180°C. This thermogram shows the solid/solid transition temperatures of the two forms.

According to one of its aspects, the present invention thus relates to a method for crystallization of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, which characterized in that: (a) the compound is dissolved by heating in a solvent selected from alkanols having 1 to 3 carbon atoms, ketones having 3 to 6 carbon atoms, dimethyl sulfoxide and ethyl acetate, said solvent optionally containing from 5 to 30% by volume of water or aqueous hydrochloric acid; (b) the resulting solution is cooled to -107+10°C at a rate of 3 to 100°C/hour with stirring at 0 to 600 rpm; and (c) the resulting product is isolated and optionally micronized.

The method according to the present invention is carried out according to conventional crystallization techniques, but the type of solvent, the cooling rate, the absence or presence of water and the stirring rate constitute essential parameters for the reproducible production of one crystalline form over another or for the reproducible production of a mixture of two forms in solids relationship.

In step (a), a 1-[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, is heated 101 381, preferably under reflux treatment, in the chosen solvent, possibly in the presence of water.

The presence of water may prove to be suitable for complete solubilization of SR 57746 A. In methanol and ethanol, for example, the product dissolves completely at a reasonable concentration (eg 15-150 g/L), while it does not completely dissolve in acetone, methyl ethyl ketone, isopropanol or ethyl acetate in the same concentrations. In these solvents, it is then sufficient to add 5 to 30% water to cause approximately complete solubilization at the reflux temperature. However, the water content must not be too high to avoid excessive dissolution and loss of end product.

According to an advantageous method, the solvent is selected from the following mixtures (vol/vol): 100/0 to 70/30 methanol/water, 100/0 to 70/30 ethanol/water, 95/5 to 70/30 acetone/water, 95/5 to 80/20 methyl ethyl ketone/water and 95/5 to 70/30 ethyl acetate/water and dimethyl sulfoxide.

As mentioned above, the concentration of SR 57746 A in the chosen solvent depends on its solubility. It can vary within the range approx. 15-100 g/L for ethyl acetate/water mixtures to 150-300 g/L for ethanol and ethanol/water mixtures.

SR 57746 A is suitably dissolved in a concentration of 5-150 g/L, preferably 100-150 g/L, in ethanol, an approx. 90/10 ethanol/water mixture or in methanol, approx. 60 g/L in an approximately 90/10 acetone/water mixture, 100-125 g/L in an approximately 95/15 methyl ethyl ketone/water mixture or approx. 15 g/L in an approximately 90/10 ethyl acetate/water mixture. Dissolution in the solvent during reflux treatment is total under these conditions.

In step (b), the obtained solution is optionally cooled with stirring, during which the cooling is monitored and, if a stirrer is used, the stirring speed is monitored since the production of a suitable crystalline form largely depends on these two parameters.

If the crystallization is carried out with stirring, the use of a paddle stirrer (hereafter also referred to as a blade stirrer) is preferred so that the entire liquid is rotated. The pipe diameter for this stirrer is between 4/5 and 2/5 of the reactor used.

The cooling rate is regulated under a temperature gradient that can range from 100 to 3°C to per hour.

The production of a particular crystalline form rather than a mixture of two forms in fixed proportions depends on the two parameters simultaneously, the stirring rate in a given solvent being generally varied as a direct function of the cooling rate.

In step (c), the product crystallized in this way is isolated, by conventional technique, after which it is possibly micronised.

The isolation of the product may, for example, allow drying of the compound obtained. It has been shown that the drying step, whether carried out in an oven or a stirred dryer, does not change the crystal structures obtained at the end of the crystallization.

By choosing the right conditions for steps (a) and (b), four different species of SR 57746 A can be isolated in step (c), namely form I, form II, form III or a form l/lll mixture. It is possible to determine the essential characteristics of the mentioned species by differential scanning calorimetry (DSC). Using thermograms recorded with a PERKIN-ELMER calorimeter under well-defined conditions, this gives:

the solid/solid transition temperature; and

the enthalpy associated with this transition.

Differential scanning calorimetry was carried out using a PERKIN-ELMER DSC7 apparatus, which was calibrated in relation to melting endotherms of indium or lead and cyclohexane. This assay was performed on 3 to 6 mg of product in an aluminum cup with a shrink-fit and perforated lid, over the temperature range of 50 to 180°C under a heating rate of 10°C/minute and using nitrogen as the purge gas.

The solid/solid transition temperature and the transition enthalpy constitute essential characteristics which in themselves are sufficient to identify each crystalline form or mixture of two of the aforementioned forms.

The aforementioned forms can also be characterized by X-ray powder diffractometry. The X-ray powder diffraction profile (Bragg diffraction angles 2 9) was determined using a SIEMENS 500 TT diffractometer with a 40 kV generator, backside monochromator, Cu k x 1 source and silicon holder over a scanning range of 4° to 40° at a speed of 1° per minute.

According to an advantageous method, step (a) is carried out by refluxing SR 57746 A in a 95/5 to 70/30 ethanol/hydrochloric acid mixture until complete dissolution, and step (b) by cooling the resulting solution to approx. 4°C under a temperature gradient of 3 to 100°C per hour, without stirring. Under this advantageous method, the crystalline form of SR 57746 A is isolated in step (c), and this is referred to hereafter as "form I" and is characterized by having: a solid/solid transition temperature of 148.4 ± 1.6°C ; and

a transition enthalpy of 26.4 ±1.1 J/g.

Form I of SR 57746 A with the above characteristics constitutes a further aspect of the present invention.

This new crystalline form was also analyzed by X-ray powder diffraction. A qualitative examination of the diffraction patterns made it possible to determine that form I has characteristic lines (2 0) at: 9.9 ± 0.3°

14.8 ±0.3°

20.8 ±0.3° (intensity: 100).

Form I is also obtained if the solution in step (b) is cooled by being left for 8-15 hours at 0-5°C, again without stirring.

According to another advantageous method, step (a) is carried out by refluxing in absolute ethanol or a 95/5 to 75/15 ethyl acetate/water mixture until complete dissolution, the SR 57746 A in this solution being present in a concentration of 10-80 g/L, preferably 70 g/L, in the ethyl acetate/water mixture or of 5-150 g/L in absolute ethanol.

Under this advantageous method, step (b) is carried out by cooling from the reflux temperature to approx. 5°C with a temperature gradient of 100 to 30°C per hour and a stirring speed of 100 to 600 rpm.

Another crystalline form is then isolated in step (c), hereafter referred to as "form II", which is characterized by having:

a solid/solid transition temperature of 153.9 1.1 °C; and

a transition enthalpy of 24.1 ±1.0 J/g.

Form II of SR 57746 A with the above characteristics constitutes a further aspect of the present invention.

This new crystalline form was also analyzed by X-ray powder diffraction. A qualitative examination of the diffraction patterns made it possible to establish that form II has characteristic lines (2 6) at:

14.5 ± 0.3° (intensity: 100)

19.3 ±0.3°

20.4 ±0.3°.

According to another advantageous method, step (a) is carried out by refluxing SR 57746 A in dimethylsulfoxide until complete dissolution, and step (b) by cooling the resulting solution with a temperature gradient of 3 to 100°C per hour and a stirring rate of 0 to 600 rpm.

Another crystalline form is then isolated in step (c), hereafter referred to as "form III", which is characterized by having:

a solid/solid transition temperature of 141 ± 2°C; and

a transition enthalpy of 17.6 ± .0.5 J/g.

Form III of SR 57746 A with the above-mentioned characteristics constitutes a further aspect of the present invention.

According to a particularly advantageous method, step (a) is carried out by heating SR 57746 A in a 95/5 to 70/30, preferably 90/10 to 85/15, ethanol/water mixture until complete dissolution, and step (b ) is carried out by cooling with a temperature gradient of approx. 5 to 30°C per hour, suitably to 5°C and a temperature gradient of 10 to 20°C per hour, preferably 10°C per hour, and a stirring speed of 0 to 600 rpm, suitably 200 to 400 rpm and preferably 400 rpm .

It has now unexpectedly been shown by differential scanning calorimetry that a

form l/form lll mixture in the weight ratio 80/20 to 60/40, suitably 70/30 to 65/35 and preferably approx. 66/34, reproducibly isolated in step (c).

This mixture consists of particles with a diameter of less than

150 micrometers.

Forms I, II and III of SR 57746 A and the mixture of Forms I and III can be micronised to give a pharmaceutical active substance with a particle size of less than 50 micrometers, suitably less than 30 micrometers and preferably less than 10 micrometers for 80% of the particles the person concerned.

The micronization can be carried out in a conventional apparatus to obtain microcrystals with a size less than 50 micrometers, for example in an ALPINE 200 AS jet mill, where SR 57746 A is introduced into the micronization chamber (diameter 200 mm) at a rate of 15 to 50 kg/hour and a working pressure of 1 to 6.5 bar, where the product is recovered in a filter bag.

The micronized crystalline forms I, II and III of SR 57746 A and the micronized mixtures of forms I and III in the ratio 80/20 to 60/40, suitably 70/35 to 65/35 and preferably approx. 66/34, constitutes a particularly advantageous aspect of the present invention.

The availability of well-defined forms of SR 57746 A or a solid

form 1/form lll mixture makes it possible to prepare pharmaceutical mixtures which have a constant and reproducible composition.

Moreover, the production of a product that has achieved fine particle size, for example by micronisation, makes it possible to significantly reduce the effective doses in order, with constant activity, to achieve the same therapeutic result.

More specifically, it has been shown that the microcrystalline form not only makes it possible to reduce the strength of the pharmaceutical mixtures, but also makes it possible to make the peroral absorption uniform and thus achieve a constant therapeutic response in any patient whether the product is administered on an empty stomach or with the food.

An investigation concerning the determination of the in vitro absorption of

SR 57746 A as a micronized form l/lll blend was made using the CACO-2 monolayer model. This test, which has been widely used as a predictive model for drug absorption by the intestinal epithelium (P. Artusson, Crit. Rev. Ther. Drug, 1991, 8:305-330) made it possible to show significant differences in terms of dissolution and permeability between SR 57746 A as a micronized form l/lll mixture and SR 57746 A obtained according to EP 0 101 381.

It appears from the results that the dissolution rate and permeability in the medium used (Hank's solution supplemented with 10% fetal calf serum and taurocholic acid) are significantly different for SR 57746 A as a micronized form l/lll mixture and for SR 57746 A obtained according to EP 0 101 381. More precisely, it was shown that the resolution and permeability are normalized - i.e. made uniform - after micronisation.

According to another aspect, the present invention thus relates to a pharmaceutical mixture which, as active ingredient, contains 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine- hydroclohd in an optionally micronized, crystalline form selected from Form I, Form II and Form III as defined above, and Form I/Form III mixtures in a ratio of 80/20 to 60/40, suitably 70/30 to 65/35 and preferably approx. 66/34.

The crystalline forms according to the invention can suitably be administered orally, parenterally, sublingually or transdermally. The amount of active substance that is administered depends on the nature and severity of the disease to be treated and on the patient's weight. The amount of active substance in the dosage unit will, however, extend up to 10 mg (calculated as free base) for the non-micronized product and may be from 0.1 to 5 mg, suitably from 0.5 to 3 mg and preferably 2 mg (calculated as free base) for the micronized product. The preferred unit doses will generally comprise 0.5, 1, 1.5, 2, 2.5 or 3 mg (calculated as free base) of micronized product.

These unit doses will normally be administered one or more times per day, for example once or twice daily, where the total dose for a human varies between 0.5 and 20 mg per day, conveniently between 1 and 10 mg per day (calculated as free base) for the non-micronized product and from 0.2 to 10 mg per day, suitably between 1 and 6 mg per day (calculated as free base) for the micronized product.

In the unit forms of the pharmaceutical mixture according to the present invention, the active substance is administered to animals and humans, preferably as a mixture with conventional pharmaceutical carriers, for the treatment of the diseases specified in particular in patents US 5,026,716, US 5,109,005,

US 5,270,320, US 5,292,745 and US 5,378,709, and in particular for the treatment of neurodegeneration, particularly amyotrophic lateral sclerosis. Suitable unit forms for administration preferably include oral forms such as tablets, which may be divisible, gelatin capsules, powders and granules as well as sublingual and buccal forms of administration. It is also possible to prepare transdermal administration forms using the new crystalline forms.

When a solid mixture is prepared in the form of tablets, the active substance is mixed with a pharmaceutical carrier, such as e.g. gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other suitable substances or treated so that they have a prolonged or delayed activity and so that they continuously release a pre-determined amount of active substance.

A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and introducing the resulting mixture into soft or hard gelatin capsules.

The active ingredient can also be formulated as microcapsules, possibly with one or more carriers or additives.

In the pharmaceutical mixtures according to the present invention, the active ingredient can also take the form of an inclusion complex in cyclodextrins, their ethers or their esters.

The following examples illustrate the invention.

EXAMPLE 1

A mixture of 19.5 g 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 is refluxed while stirring until complete dissolution, after which it is allowed to cool with continuous stirring. When the first crystals start to form (at approx. 63°C), the stirrer is stopped, and the reaction mixture is kept at 0-5°C overnight. After filtration, the product is transferred twice to a paste in 30 mL of absolute ethanol and 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-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (SR 57746 A - form I).

According to differential scanning calorimetry, it had SR 57746 A - form I obtained by this preparation:

a solid/solid transition temperature of 148-149°C; and

a transition enthalpy of 26.4 J/g.

The corresponding thermogram is shown in Figure 1.

By X-ray powder diffraction analysis with a SIEMENS 500 TT diffractometer under the above conditions, the SR 57746 A - form I obtained by this preparation has characteristic lines (Bragg angles 2 0) at 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 lines collected in Table 1, together with the relative intensity expressed as a percentage of the most intense line.

EXAMPLE 2

In a METTLER RC1 calorimetric reactor equipped with a blade stirrer with a diameter of 8 cm, a mixture of 70 g of crude 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6 -tetrahydropyridine hydrochloride and 1 L of absolute ethanol until the product is completely dissolved. The resulting solution is cooled to 10°C under a cooling rate of 80°C per hour and a stirring speed of 500 rpm. The resulting precipitate is filtered off 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) was obtained.

According to differential scanning calorimetry, it had SR 57746 A - form I obtained by this preparation:

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

a transition enthalpy of 24.1 J/g.

The corresponding thermogram is shown in Figure 2.

By X-ray powder diffraction analysis with a SIEMENS 500 TT diffractometer under the above conditions, the SR 57746 A - form II obtained by this preparation has characteristic lines (Bragg angles 2 0) at 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 representation is given by the significant lines collected in Table 2, together with the relative intensity expressed as a percentage of the most intense line.

EXAMPLE 3

A mixture of 2 g of crude 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride and 50 mL of dimethylsulfoxide is refluxed until complete dissolution, after which the mixture is is cooled overnight and the crystalline product is isolated and dried under vacuum at 45°C overnight.

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.

According to differential scanning calorimetry, it had SR 57746 A - form III obtained by this preparation:

a solid/solid transition temperature of 141-142°C; and

a transition enthalpy of 17.6 J/g.

The corresponding thermogram is shown in Figure 3.

EXAMPLE 4

A mixture of 100 g crude 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride and 1 L 90/10 ethanol/water mixture is refluxed while stirring until the product is completely dissolved. The resulting solution is cooled from reflux temperature to 5°C with stirring at 400 rpm with blade stirrers and a cooling rate of 10°C/hour. The resulting crystalline product is filtered off and dried at 45°C under vacuum overnight.

Under these conditions, 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (SR 57746 A - form III) was obtained as a form l/ form III mixture in the ratio 65.7/34.3 (SR 57746 A - form I/III).

By differential scanning calorimetry, SR 57746 A - form I/Ill obtained in this preparation gave a thermogram which is shown in Figure 4 and which shows only the two characteristic peaks corresponding to forms I and III.

EXAMPLES 5 and 6

The procedure was as described in Example 2, and in two different preparations the cooling rate and stirring rate were varied as follows: cooling at 100°C/hour and stirring at 600 rpm (Ex. 5);

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

Under these conditions, SR 57746 A - form II was obtained.

When working in absolute ethanol at a concentration of 70 g/L, it has been shown that the formation of form II depends on cooling rate and stirring rate according to a first-degree equation of the type y=ax+b.

To obtain Form II under these conditions, the equation is as follows:

Rmax <=> 4.23V<+> 170.51

where Rmax is the stirring speed in rpm and V is the cooling speed in °C/hour. Consequently, to achieve form II, the stirring rate must be less than or equal to Rmax for a given cooling rate.

EXAMPLE 7

A mixture of 15 g of crude 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride and 1 L of a 90/10 ethyl acetate/water mixture is refluxed until the product is completely dissolved while stirring with a blade stirrer with a diameter of 8 cm. The resulting solution is cooled to 5°C at 60°C per hour with a stirring rate of 150 rpm, whereupon the resulting precipitate is filtered off and dried under vacuum to give SR 57746 A - form II, which is identical to the product obtained in Example 2.

EXAMPLE 8-11

In four different preparations, crude 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride is refluxed at a concentration of 70 g/L in a 92/ 8 ethyl acetate/water mixture (reaction volume: 1.3 L) in an RC 1 reactor connected with a PARTEC<®> 100 particle monitor from LASENTEC and equipped with a blade stirrer with a diameter of 8 cm. After complete dissolution, the solution was cooled under the following conditions for the respective four preparations: cooling at 100°C/hour and stirring at 400 rpm (Ex. 8);

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

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

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

Under these conditions, SR 57746 A - form II was obtained.

When working in a 92/8 ethyl acetate/water mixture at a concentration of 70 g/L, it has been shown that the formation of form II depends on cooling rate and stirring rate according to the following first-order equation:

where Rmax is the stirring speed in rpm and V is the cooling speed in °C/hour.

To achieve form II, the stirring rate must therefore be less than or equal to Rmax for a given cooling rate.

EXAMPLE 12

Crude 1 -[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride at a concentration of 60.6 g/L in a 90/10 acetone/ water mixture is refluxed while stirring until complete dissolution. The procedure described in Example 4 is then followed to give SR 57746 A - form I/III in a ratio of 80/20.

EXAMPLE 13

Crude 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride in a concentration of 100 g/L in methanol is refluxed with stirring until complete dissolution. The procedure described in Example 4 is then followed to give SR 57746 A - form I/III in a ratio of 80/20, which is identical to the product from Example 12.

EXAMPLE 14

Crude 1 -[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride at a concentration of 100 g/L in a 70/30 ethanol/water mixture is refluxed while stirring until complete dissolution. The procedure described in Example 4 is then followed to give SR 57746 A - form I/II in a ratio of 65.7/34.3, which is identical to the product from Example 4.

EXAMPLE 15

24 kg SR 57746 A - form I/III described in Example 4 is introduced into the micronization chamber (diameter 200 mm) in an ALPINE 200 AS jet mill at a speed of 25 kg/hour and a working pressure of 6.5 bar, and the thereby micronized product is recovered in a filter bag. This gives SR 57746 A - form I/III with a particle size distribution such that all the particles have a size of less than 20 micrometres and 85% of the particles have a size of less than 10 micrometres.

Differential scanning calorimetry of the resulting micronized product shows that the transition temperatures are not affected by micronization. These transitions are of the fixed/fixed type. SR 57746 A degrades before melting, which starts at 250°C.

EXAMPLE 16

Pharmaceutical mixture which, as active ingredient, contains SR 57746 A -form l/III (micronized) according to Example 15 above:

The active substance is sieved at 0.2 mm and then mixed with the excipients. The mixture is sieved at 0.315 mm, mixed again and sieved again at 0.315 mm. After a final mixing, the mixture is transferred to gelatin capsules No. 3 in an amount of 170 mg of mixture 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.

Claims (1)

1. Method for crystallization of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenylO-1^,S.e-tetrahydropyridine hydrochloride (SR 57746 A), characterized in that: (a) said compound is dissolved by heating in a solvent selected from alkanols having 1 to 3 carbon atoms, ketones having 3 to 6 carbon atoms, dimethyl sulfoxide and ethyl acetate, said solvent optionally containing from 5 to 30% water or aqueous hydrochloric acid; (b) the resulting solution is cooled to -10/+10°C at a rate of 3 to 100°C/hour with stirring at 0 to 600 rpm; and (c) the resulting product is isolated and optionally micronized. 2. Method according to claim 1, characterized in that step (a) is carried out by refluxing SR 57746 A in a 95/5 to 70/30 ethanol/hydrochloric acid mixture until complete dissolution, and step (b) is carried out by cooling the resulting solution to approx. 4°C under a temperature gradient of 3 to 100°C per hour, without stirring, and Form I of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6 -tetrahydropyridine hydrochloride is isolated in step (c). 3. Method according to claim 1, characterized in that step (a) is carried out by reflux treatment of SR 57746 A in absolute ethanol or a 95/5 to 75/15 ethyl acetate/water mixture until complete dissolution, the said compound in this solution being present in a concentration of 10-80 g/L in the ethyl acetate/water mixture or 5-150 g/L in absolute ethanol, step (b) is carried out by cooling from the reflux temperature to approx. 5°C under a temperature gradient of 100 to 30°C per hour and a stirring speed of 100 to 600 rpm, and Form II of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1, 2,3,6-tetrahydropyridine hydrochloride is isolated in step (c). 4. Method according to claim 1, characterized in that step (a) is carried out by reflux treatment of SR 57746 A in dimethylsulfoxide until complete dissolution, and step (b) is carried out by cooling the resulting solution under a temperature gradient of 3 to 100°C per hour and a stirring speed of 0 to 600 rpm, and Form III of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride is isolated in step (c ). 5. Method according to claim 1, characterized in that step (a) is carried out by reflux treatment of SR 57746 A in a 95/5 to 70/30 ethanol/water mixture until complete dissolution, step (b) is carried out by cooling the resulting solution under a temperature gradient of 5 to 30°C per hour and a stirring speed of 0 to 600 rpm, and a Form 1/III mixture of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)- 1,2,3,6-tetrahydropyridine hydrochloride in a ratio of 80/20 to 60/40 is isolated in step (c). 6. Method according to claim 5, characterized in that a 90/10 ethanol/water mixture is used in step (a), step (b) is carried out by cooling the resulting solution to 5°C under a temperature gradient of 10 to 20°C per hour and a stirring speed of 200 to 400 rpm, and a Form 1/III mixture of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine -hydrochloride in a ratio of 70/30 to 65/35 is isolated in step (c). 7. Process according to claim 6, characterized in that the temperature gradient is 10°C per hour and the stirring speed is 400 rpm in step (b), and a form l/lll mixture of 1-[2-(2-naphthyl)ethyl]- 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride in a ratio of approx. 66/34 is isolated in step (c). 8. Method according to one of claims 1 to 7, characterized in that a blade stirrer is used. 9. Form I of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, obtained according to claim 2. 10. Form II of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, obtained according to claim 3. 11. Form III of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, obtained according to claim 4. 12. Mixture of form I and form III of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, obtained according to one of claims 5 to 7. 13. Form I of 1-[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; and a transition enthalpy of 26.4 ±1.1 J/g. 14. Form I according to claim 13, characterized in that its X-ray powder diffraction pattern has characteristic lines (Bragg angles 2 0) at: 9.9 ±0.3° 14.8 ±0.3° 20.8 ±0.3° (intensity: 100). 15. Form II of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, characterized in that it has: a solid/solid transition temperature of 153.9 ± 1.1 °C; and a transition enthalpy of 24.1 ±1.0 J/g. 16. Form II according to claim 15, characterized in that its X-ray powder diffraction pattern has characteristic lines (Bragg angles 2 0) at: 14.5 ±0.3° (intensity: 100) 19.3 ±0.3° 20.4 ± 0.3°. 17. Form III of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, characterized in that it has: a solid/solid transition temperature of 141 ± 2°C; and 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 form III according to claim 17, in a form l/form lll ratio of 80/20 to 60/40. 20. Mixture according to claim 19 in a form 1/form III ratio of 70/30 to 65/35. 21. Mixture according to claim 20 in a form l/form III ratio of approx. 66/34. 22. Mixture according to any one of claims 19 to 21, characterized in that it is micronized. 23. Pharmaceutical mixture which, as active ingredient, contains 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride in an optionally micronized, crystalline form selected from form I, form II, form II, form III and form l/lll mixtures according to any one of claims 9 to 21. 24. Mixture according to claim 23, characterized in that the active substance is a mixture according to claim 22, in the form of a unit dose. 25. Mixture according to claim 24, characterized in that each unit dose contains an amount of micronized active substance corresponding to a dose selected from 0.5, 1, 1.5, 2, 2.5 and 3 mg of free base.