HK1063621B - Crystalline form of a phenylethanolamine, the preparation thereof and pharmaceutical compositions comprising the same - Google Patents

Description

The present invention relates to a new crystalline form, hereinafter referred to as form B, of hydrochloride of [(7S) 7-[(2R) 2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7,8-tetrahydronaphtalen-2-yloxy]ethyl acetate, its preparation and the pharmaceutical compositions containing it.

This compound, which was formerly called N-[(2S)-7-ethoxycarbonylmethoxy-1,2-ethylamethoxy-1,2,3,4-tetrahydronapht-2-yl]-(2R) -(3-chlorophenyl)-2-hydroxyethaneamine, and designated SR 58611A, and its preparation and activity on gut motor function were described in EP 303546, example 12. Subsequently, this compound was shown to have exceptional activity on the central nervous system, allowing its use as an antidepressant to be considered (EP 0489640).

It has now been found that this compound exists in three polymorphic forms, I, II and III, hereinafter referred to as forms A, B and C respectively, one of which, called form B, has physical properties which are advantageous for the preparation of a medicinal product on an industrial scale.

The compound SR 58611A is described in Example 12 of EP 0303546 as a vitreous solid (fusion temperature indeterminate), having a rotational power of -72.9° (c=0.5%, methanol), with 4 displacement values per NMN 1H and 3 peak characteristic IR. It is here, as was later found, a mixture of the three polymorphs A, B and C, with probably a majority of the A form since the 1203 cm-1 absorption peak indicated is specific to it (in fact 1206 cm-1 according to a more precise measurement).

The three polymorphic forms A, B, C of the compound referred to as SR 58611A can now be clearly differentiated: Melting points determined by differential scanning thermal analysis (DSC): Form A (or form I) : pF = 158+/-2°Cform B (or form II) : pF = 129+/-2°Cform C (or form III): pF = 120+/-2°C.Infrared spectra, characteristic peak absorption: A: 2816 cm-1, 2740 cm-1, 1745 cm-1, 1206 cm-1, B: 2780 cm-1, 2736 cm-1, 1722 cm-1, 1211 cm-1, C: 2801 cm-1, 2750 cm-1, 1760 cm-1, 1200 cm-1. Similarly, the X-ray diffraction diagrams of the powders of each shape are specific.

Thus, the present invention relates to the B form of the hydrochloride of [(7S) 7-[(2R) 2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7,8-tetrahydronaphtalen-2-yloxy]ethyl acetate which has, inter alia, the following physical characteristics: The compound is more particularly characterized in the Appendices, Figures 1 and 2:Figure 1 represents the infrared spectrum of the B-shaped compound according to the invention; and Figure 2 represents the X-shaped compound's diffraction diagram on powder (obtained with a Cu Kα 1 source in a configuration/θ, monochrome rear peak).

For the purposes of this description and the claims, Form B of SR 58611A or compound of the invention means a product containing at least 95% by weight and preferably at least 99% by weight of Form B next to other polymorphs.

The invention also includes a method of preparation of the compound according to the invention, characterized by adding a solution of concentrated HCl to a solution of [(7S) 7-[(2R) 2-(3-chlorophenyl) 2-hydroxyethylamino]-5,6,7,8-tetrahydronaphtalen-2-yloxy]ethyl acetate in a solvent selected from propan-2-ol, 2-methylpropan-2-ol and butan-2-ol at a temperature of 40 to 70 °C, initiating crystallization by seeding with a small amount of the B-form, and then gradually cooling the solution.

Preferably, crystallization is carried out at a temperature of 50 to 70°C.

The solvent is preferably propane-2-ol.

Concentrated hydrochloric acid may be the commercial type, generally 35 to 38% by weight.

The compound of the invention may also be prepared by a recrystallization process, characterized by suspension of the hydrochloride of [(7S) 7-[(2R) 2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7,8-tetrahydronaphtalen-2-yloxy]ethyl acetate, in raw form or a mixture of crystalline forms, in propan-2-ol, 2-methylpropan-2-ol or butan-2-ol at a temperature of 70°C and maintenance of the suspension in isotherm until the crystals are transformed into B-form.

If no primer is available, however, it is possible to achieve spontaneous transformation to B by keeping the other crystalline forms or mixtures in suspension, particularly in an alcohol as mentioned above, for a sufficient time depending on the temperature, particularly between room temperature and below the boiling point of the alcohol.

According to another variant, the product of the invention may be prepared by heating a solution of hydrochloride of [(7S) 7-[(2R) 2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7,8-tetrahydronaphtalen-2-yloxy]ethyl acetate in an organic solvent such as an alcohol or ketone to a temperature of 45 to 70 °C, concentration of the solution by evaporation or distillation, and then gradual cooling of the solution by agitation to a temperature of 10 to 40 °C.

In fact, it was unexpectedly found that form B is the most thermodynamically stable form at room temperature or more generally at a temperature of 70°C or below, because other forms A and C or their mixtures eventually turn into form B when kept in solution or suspension at a certain temperature for a sufficiently long time (see examples 3 and 4), regardless of the solvent.

The following examples illustrate the invention.

Example 1: Preparation of the B form of SR58611 hydrochloride (SR58611A).

Add 1 equivalent of concentrated hydrochloric acid to a propane-2-oleic solution of SR58611 base (obtained by EP0303546) at a concentration of 100 g/l at room temperature. Agitate the mixture to 70°C to dissolve all germs that may have formed and perform a linear cooling ramp to 50°C (+/- 2°C). Once this temperature is reached, start crystallization with 2% SR58611A seed B. Maintain the isothermal agitation suspension at this temperature for one hour and then cool the product by controlled cooling ramp to 20°C to allow recovery to more than 90% B. The product is separated from the water by filtration to give a melting medium of SR58611A in the form of B-2-hydrochlorite, at a pressure of IR505-130°C.

The test chemical is used to determine the concentration of the test chemical in the test medium.

SR58611 hydrochloride polymorph mixture (200 g) obtained by EP0303546 is solubilised in 1.6 litres of propan-2-ol at 80°C. Add 2% (relative to the mass of SR58611A introduced) of black CX activated carbon and keep the suspension agitated at 80°C for 15 minutes.

Once the distillation is completed, the homogeneous medium is cooled to 60°C with a linear cooling ramp of -20°C/h under agitation (Impeller - PN = 120W/m3). Once the temperature of 60°C is reached, the medium is started with 2% (relative to the mass of SR58611A introduced) of SR58611A B-form suspended in propanol-2-.

After 1 hour of isothermal heating at the seed temperature, cool the suspension to 20°C with a linear cooling ramp of -10°C/h.

The product is separated by filtration, washed with propane-2-ol (1 x 400 ml) and dried at 50°C at reduced pressure to give SR58611 hydrochloride of form B (190 g), melting point 125-130°C.

Example 3: Kinetic transformation of SR58611A polymorphic mixture into B.

The polymorph SR58611 hydrochloride (4.46 g) is suspended at room temperature in 0.3 litres of propane-2-ol. After 70 h of isothermal heating, the suspension is SR58611A hydrochloride, form B, > 96%.

Example 4: Kinetic transformation of SR58611A polymorphic mixture into B.

The polymorph SR58611 hydrochloride (95.2 g) is suspended at 70 °C in 0.3 litres of propane-2-ol. After 12h30 of isothermal heating, the suspension is SR58611 hydrochloride B form, > 98%.

Example 5: Industrial preparation of SR58611A of shape B.

A dry, nitrogen-purged reactor is loaded with 24.7 kg of SR58611A polymorph mixture (pF=159°C), 185 I of propane-2-ol and heated to 75°C (total dissolution temperature 68°C). Then 0.49 kg of CX activated carbon and 5 I of propane-2-ol are introduced and the temperature is raised to 80°C for 30 minutes. Then the contents are kept at 75-78°C by nitrogen pressure, the tank is rinsed with 7 I of solvent and kept for another 10 minutes at 78°C, then the medium is vacuumed under atmospheric pressure to a residual volume of 99 I. in about 1 hour. The medium is cooled to 60°C (closed at 0°C; 0.43% of the R2 is removed for 30 minutes); 0.4 and 0.4 per cent of the R2 is produced with a medium of propane-ol and a dry product is immediately washed at 70°C (R2 is produced at 0.2 and 0.4 per cent of the R2 is removed at 60°C).

Example 6: Comparison of drying

Drying in a shaker filter of a wet SR58611A A-form filter cake in less than two hours results in a change in crystalline shape and a cake made up of 90% C-form. To return to A-form, drying at a temperature above 60°C under shaking must then be continued for approximately 48 hours.

The advantage of form B is that it does not change crystalline shape when dried, and the shape of the crystals obtained (thick hexagonal flakes) reduces the residual moisture content of the filter cake to less than 20% and thus facilitates the drying of the product for use as an active ingredient in medicines.

Example 7: Pharmaceutical composition.

The product of the invention may be administered for the treatment of depression at a dose of 100 to 800 mg/day (based on the baseline calculation), including 300 to 600 mg/day by mouth, depending on the severity of the disease and the weight of the patient.

Typical formulations are tablets or capsules or dredges. - What?

SR58611A forme B	100	200
Lactose monohydrate	330,5(QS)	217,3
Hydroxypropylméthylcellulose	4,2	8,4
Stéarate de magnésium	6,3	6,3
Total (mg)	450	450

Claims (11)

1. B form of ethyl [(7S)-7-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7,8-tetrahydronaphth-2-yloxy]acetate hydrochloride, the infrared spectrum of which exhibits the following characteristic absorption peaks: 2780, 2736, 1722, 1211 cm^-1.
2. B form of ethyl [(7S)-7-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7,8-tetrahydronaphth-2-yloxy]acetate hydrochloride having a melting point of 129+/-2°C, determined by differential scanning calorimetry.
3. B form of ethyl [(7S)-7-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7,8-tetrahydronaphth-2-yloxy]acetate hydrochloride, the powder X-ray diffraction diagram of which exhibits the following characteristic lines: 7.69, 9.83, 13.95, 16.58, 18.70, 20.40, 21.57, 23.40, 24.15 and 25.64.
4. Process for the preparation of the compound according to Claims 1 to 3, characterized in that a solution of concentrated HCl is added to a solution of ethyl [(7S)-7-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7,8-tetrahydronaphth-2-yloxy]acetate in a solvent chosen from propan-2-ol, 2-methylpropan-2-ol and butan-2-ol at a temperature ranging from 40 to 70°C, crystallization is initiated by seeding with a small amount of the B form and then the solution is gradually cooled.
5. Process according to Claim 4, characterized in that the crystallization is carried out at a temperature of 50 to 70°C.
6. Process according to Claim 4 or 5, characterized in that the solvent is propan-2-ol.
7. Process for the preparation of the compound according to Claims 1 to 3, characterized in that ethyl [(7S)-7-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7,8-tetrahydronaphth-2-yloxy]acetate hydrochloride is suspended in propan-2-ol, 2-methylpropan-2-ol -or. butan-2-ol at a temperature ranging from ambient temperature to 70°C and the suspension is maintained under isothermal conditions until the crystals have been converted to the B form.
8. Process for the preparation of the compound according to Claims 1 to 3, characterized in that a solution of ethyl [(7S)-7-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7,8-tetrahydronaphth-2-yloxy]acetate hydrochloride in an organic solvent chosen from an alcohol or a ketone is heated to a temperature of 45 to 70°C, the solution is concentrated by evaporation or distillation and then the solution is gradually cooled with stirring to a temperature of 10 to 40°C.
9. Process according to Claim 8, characterized in that the solvent is propan-2-ol.
10. Pharmaceutical composition, comprising the compound according to Claims 1 to 3 as active principle and one or more pharmaceutically acceptable excipients.
11. Medicament, characterized in that it comprises the compound according to Claims 1 to 3.