EP1984341A1

EP1984341A1 - Rimonabant monohydrate, process for the preparation thereof and pharmaceutical compositions containing same

Info

Publication number: EP1984341A1
Application number: EP07730917A
Authority: EP
Inventors: Olivier Monnier; Gérard Coquerel; Baptiste Fours; Hélène DUPLAA; Philippe Ochsenbein
Original assignee: Sanofi Aventis France
Current assignee: Sanofi SA
Priority date: 2006-02-08
Filing date: 2007-02-05
Publication date: 2008-10-29
Also published as: EA200870236A1; MA30312B1; TW200804343A; CN101405271A; FR2897060B1; NO20083521L; AR059327A1; US20090048449A1; KR20080093042A; DOP2007000023A; WO2007090949A1; BRPI0707711A2; ZA200806713B; IL192963A0; JP2009526025A; AU2007213649A1; CA2641494A1; UY30137A1; GT200700014A; FR2897060A1

Abstract

The present invention relates to rimonabant monohydrate, to the process for preparing it and to the pharmaceutical compositions containing it.

Description

RMONABANT MONOHYDRATE, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME.

The subject of the present invention is rimonabant monohydrate, its process of preparation and the pharmaceutical compositions containing it.

Rimonabant is the international non-proprietary name for N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide.

This compound, its salts and its solvates are described in European Patent 656354. A polymorphic crystalline form of rimonabant called Form II is described in International Application WO2003 / 040105.

We have now found a particular solvate: rimonabant monohydrate which has advantageous properties.

By rimonabant monohydrate is meant the chemical compound consisting of a rimonabant molecule and a molecule of water.

Rimonabant monohydrate preferentially exists in crystallized form. The present invention relates to rimonabant monohydrate, and more particularly to a crystalline form of rimonabant monohydrate.

Obtaining a solvate of rimonabant with a molecule of water is particularly advantageous because rimonabant monohydrate is an active ingredient that can be administered to humans.

The crystalline form of rimonabant monohydrate constitutes a powder whose characteristics are improved compared with powders constituted either by the crystalline form I of rimonabant or by the crystalline form II of rimonabant. Thus, during the isolation of the rimonabant monohydrate crystals by filtration from the solution in which they have formed, surprisingly, a better filterability is observed than when it comes to filtering crystals of Form I or form II crystals of rimonabant. The improved filterability makes it possible to shorten the filtration step and brings about a significant improvement in the texture of the filter cake, which is characterized by a low moisture content of the powder before drying and a low level of residual solvent before drying. The resulting powder after drying has improved physical properties, particularly in terms of flowability and therefore of handling.

Improved filterability is measured by studying the characteristics of the filter cake: for crystalline form rimonabant monohydrate, It is observed that this has a lower specific resistance than that measured for crystalline form I and for crystalline form II of rimonabant.

The flowability of the crystalline form of rimonabant monohydrate was measured and compared to that of crystalline form II of rimonabant. The flowability of the crystalline forms is measured by the flowability index or compressibility index or Carr index as described in R.L. Carr: Evaluation of Flow Properties of Solids, Chem. Eng., 1965, 163-168 as well as in the European Pharmacopoeia.

The flowability index is calculated according to the following ratio: IC = 100 x (pt - pb) / pt where pt is the density typed, and, pb the gross density. This index is considered good if it is less than 20.

The densities are determined experimentally by compacting the product in a graduated cylinder according to the procedure described in the European Pharmacopoeia. The densities are determined after 10, 500, 1250 and 2500 shots. The Carr index is determined from the data measured at 10 and 1250 counts.

An index of Carr less than or equal to 20% is considered to correspond to a good flow of the powders, while a Carr index greater than 21% is considered as corresponding to a passable flow of powders, or difficult or very difficult. For the crystalline form of rimonabant monohydrate, an index of

Carr equal to 20%, that is to say good, while for the crystalline form II of rimonabant, we measure a Carr index of the order of 38%, that is to say very difficult. The Carr index measured for the crystalline form I of rimonabant also corresponds to a very difficult flowability. The good flowability index of the crystalline form of rimonabant monohydrate indicates that this form can easily be mixed with excipients during the preparation of pharmaceutical compositions for the administration of rimonabant monohydrate. In particular, during the preparation of tablets, the flow of the powder is improved and the content of active ingredient is better controlled. Thanks to the better flowability, the tableting process can be simplified by eliminating certain steps such as wet granulation, drying and calibration, which increases the rates and reduces the cost of production.

The present invention also relates to the process for obtaining rimonabant monohydrate. This process is characterized in that the rimonabant in an organic solvent and water is added. More particularly, this process is characterized in that: a) a mixture of rimonabant is prepared in a solvent chosen from:

methylcyclohexane, acetonitrile,

4-methyl-2-pentanone,

- acetone,

- toluene,

- dimethylsulfoxide, - or a mixture of these solvents; b) water is added dropwise.

In particular, in step a), a solvent chosen from:

methylcyclohexane,

acetonitrile, 4-methyl-2-pentanone,

- acetone,

- or a mixture of these solvents;

Preferably, according to the method of the invention, step a) is carried out at room temperature. In particular, the process for preparing rimonabant monohydrate according to the invention is characterized in that: a) a saturated solution of rimonabant is prepared in a solvent chosen from:

methylcyclohexane,

acetonitrile, 4-methyl-2-pentanone,

- acetone,

- toluene,

dimethylsulfoxide,

- or a mixture of these solvents; b) adding water dropwise; c) isolating the formed rimonabant monohydrate.

In particular, in step a), a solvent chosen from:

methylcyclohexane,

acetonitrile, 4-methyl-2-pentanone,

- acetone, - or a mixture of these solvents;

Preferably, after step a), it is filtered to obtain a clear saturated solution.

The rimonabant monohydrate formed by the process according to the invention is isolated by filtration.

In particular, in step a), a solution of rimonabant in acetone is prepared. More particularly, a solution containing between 150 and 200 g / l of rimonabant in acetone is prepared, and preferably a solution containing 200 g / l of rimonabant in acetone. In particular, in step b), water is added dropwise so as to obtain an acetone / water mixture containing between 10 and 30% water by volume; preferably, the mixture contains 20% water.

A process for obtaining rimonabant monohydrate in crystalline form is characterized in that: a) a mixture of rimonabant is prepared in a solvent chosen from:

methylcyclohexane,

acetonitrile,

4-methyl-2-pentanone,

acetone, toluene,

dimethylsulfoxide,

- or a mixture of these solvents; b) adding water dropwise; c) cooling between 0 ° C and 15 ° C; d) the crystals formed are filtered.

In particular, in step a), a solvent chosen from:

methylcyclohexane,

acetonitrile,

4-methyl-2-pentanone, acetone,

- or a mixture of these solvents;

In particular, the process for preparing rimonabant monohydrate in crystalline form is characterized in that: a) a saturated solution of rimonabant in a solvent chosen from:

methylcyclohexane, acetonitrile,

4-methyl-2-pentanone,

- acetone,

toluene, dimethylsulfoxide,

- or a mixture of these solvents; b) adding water dropwise; c) cooling between 0 ° C and 15 ° C; d) the crystals formed are filtered. In particular, in step a), a solvent chosen from:

methylcyclohexane,

acetonitrile,

4-methyl-2-pentanone,

acetone, or a mixture of these solvents;

Preferably, after step a), it is filtered to obtain a clear saturated solution.

More particularly, the rimonabant monohydrate can be prepared in crystalline form according to a process characterized in that: a) a mixture containing between 150 and 200 g / l of rimonabant in acetone is prepared at room temperature, preferably 200 g / l; b) is added dropwise between 10% and 30% water by volume, preferably 20% water by volume; c) is cooled to a temperature between 0 ° C and 15 ° C, preferably 5 ° C; d) the crystals formed are filtered.

After step a), the formed mixture can be filtered to obtain a clear saturated solution.

After filtration of the last step, the product obtained is dried at a temperature between room temperature and 40 ^° C., preferably at room temperature.

Preferably, the solvent used in step a) of the process according to the invention is acetone, which leads to isolating the rimonabant monohydrate from an acetone / water mixture, this mixture has conductive and its use makes it possible to avoid the accumulation of electrostatically dangerous charges on the industrial level. Rimonabant monohydrate is characterized by various elements of its physicochemical analysis.

Water content :

Rimonabant monohydrate is characterized by elemental analysis and analysis of the water content measured on a Karl Fisher apparatus.

Elemental analysis: C22H23O2N4Cl3.

The theoretical and measured values take into account the presence of a molecule of water.

Measured water content: 3.7% ± 0.5%; calculated: 3.74%.

The water content indicates the presence of the equivalent of one molecule of water per molecule of product.

Thermogravimetry:

Thermogravimetric analysis was carried out for rimonabant monohydrate by a thermogravimetric analysis device TGA 2950, marketed by TA Instruments SARL (PARIS, France); it is operated under a nitrogen atmosphere, the initial temperature is 30 ° C, it increases at a rate of 10 ° C / minute until decomposition of the product.

The theoretical loss of mass corresponding to one mole of water is 3.74%. Experimentally by thermogravimetric analysis, it is equal to 3.55%. This result is in agreement with the theory and confirms that the test product contains a molecule of water which starts in the same zone in temperature by differential enthalpy analysis, namely between 40 ^° C. and 100 ° C. (FIG.

The thermo gravimetric mass loss curve indicates that the water molecule present is a hydration molecule.

The crystalline form of rimonabant monohydrate has also been analyzed and characterized.

Differential Scanning Calorimetry:

The differential enthalpy analysis of the crystalline form of rimonabant monohydrate is carried out under the same conditions on an MDSC 2920 differential enthalpy analysis apparatus, marketed by TA Instruments SARL (PARIS, France); it operates under a nitrogen atmosphere, the initial temperature is 30 ^° C., it increases at a rate of 10 ° C./minute. We compare with the results obtained under the same conditions for the crystalline form II of rimonabant.

For each compound, the melting peak and the enthalpy difference of the substance (ΔH) are measured before and after melting, in Joule per gram of material.

According to FIG. 2, the crystalline form II has a melting peak at 157 ± 2 ^° C. with ΔH = 66 ± 2 J / g.

According to FIG. 3, the crystalline form of the rimonabant monohydrate loses its water of crystallization molecule between 40 ^° C. and 100 ^° C. It simultaneously has a melting peak of between 95 ° C. ± 5 ° C. and 115 ° C. 5 ° C.

The water vapor sorption / desorption measurement analysis is carried out on the crystalline form of rimonabant monohydrate on an SGA100 analysis apparatus marketed by VTI (USA). It operates between 0% and 100% relative humidity at 25 ⁰ C after degassing the monohydrate form at 80 ^° C. for 3 hours. Rimonabant monohydrate loses its water of hydration molecule during drying at 80 ° C. During the water vapor sorption cycle, the conversion of rimonabant to rimonabant monohydrate occurs from 40% relative humidity. The sorption / desorption isotherm is shown in FIG.

According to the present invention, the crystalline form of rimonabant monohydrate is also characterized by its infra-red spectrum (LR.). This is compared with that of the crystalline form II of rimonabant previously described.

The infrared spectra (LR.) Of these two crystalline forms of rimonabant are recorded on Perkin Elmer System 2000 FT-IR spectrophotometers, between 400 cm and 4000 cm, with a resolution of 4 cm, in a potassium bromide pellet. the test compound being at a concentration of 0.5% by weight.

These spectra are characterized by the absorption bands reported in Tables 1 and 2 below.

TABLE 1: I.R. Spectrum, Crystalline form of rimonabant monohydrate

TABLE 2: LR spectrum. , Crystalline form II of rimonabant

The broad band observed from 3637 to 3208 cm ^-1 on the IR spectrum of the crystalline form of rimonabant monohydrate (FIG. 5) corresponds to the vibration of the HOH bonds of the hydrate and constitutes one of the characteristics of said IR spectrum.

For the rest of the IR spectra, by comparing FIGS. 5 and 6 where they are represented, slight differences are observed at the positions and / or the intensities of the lines, but the two spectra have the same general appearance.

Thus the IR spectrum of the crystalline form of rimonabant monohydrate characterized by the following absorption bands: λ (cm) = 3637; 3385; 1658; 1554; 1496; 990; 780 and more particularly by the bands λ = 3637 cm ^", 3385 ^cm"1; 1658 cm ^-1 , 1554 cm ^-1 and 1496 cm ^-1 .

The crystalline form of rimonabant monohydrate is also characterized by the characteristic lines of the X-ray powder diffractogram.

The X-ray diffraction pattern (X-ray) of the powder (diffraction angle) is established with a Siemens D500TT (theta / theta) diffractometer, Bragg-Brentano type; CuKoq source, λ = 1, 5406A; scanning range 2 ° to 40 ° at 1 ° per minute in 2 Bragg theta.

The characteristic lines of the diffractogram are reported in the following Table 3:

TABLE 3:

X-ray powder, crystalline form of rimonabant monohydrate

Under the same conditions, the characteristic lines of the powder X-ray diffractogram of crystalline form II of rimonabant are recorded, the characteristic lines are reported in Table 4 below:

TABLE 4: X-rays on powder, crystalline form II of rimonabant

The corresponding diffractograms are reproduced in FIGS. 7 and 8. The crystalline form of rimonabant monohydrate is also characterized by its crystalline structure for which the mesh parameters have been determined by single-crystal X-ray diffraction.

TABLE 5: Mesh Parameter, Crystalline Form of Rimonabant Monohydrate

The values () in the right column are the standard deviations observed for this measurement.

In FIG. 9, the theoretical and experimental diffractograms of rimonabant monohydrate are compared by superposition.

From the mesh parameters and the atomic coordinates x, y, z of the atoms of the molecule, calculation software makes it possible to draw projected views of the crystal lattice of the molecule concerned.

As can be seen in FIG. 10, this representation of the molecule in the crystalline mesh demonstrates the presence of the water molecule that participates well in the crystalline structure (water of crystallization).

Example: preparation of the crystalline form of rimonabant monohydrate.

80 g of rimonabant form II are suspended in 400 ml of acetone at room temperature with stirring overnight. The suspension is filtered with _{2β in} order to obtain a solution of rimonabant in saturated and clear acetone.

100 ml of water are introduced into this solution, which causes the progressive insolubilization of rimonabant monohydrate in crystalline form. The suspension obtained is cooled to 5 ° C. and then filtered. The product is dried at room temperature for 48 hours.

65 g of the expected compound are obtained, the water content of which is 3.4%, which corresponds to the theoretical water content (3.7%).

The rimonabant titer of the compound obtained is 96.6%. Thus, it appears that no impurity is quantifiable in the compound obtained.

The RX Powder Diagram is shown in Figure 11.

30

35

Claims

1. Rimonabant monohydrate.

2. The crystalline form of rimonabant monohydrate according to claim 1 characterized by a melting peak of between 95 ° C + 5 ° C and 115 ° C ± 5 ° C.

3. The crystalline form of rimonabant monohydrate according to claim 1, characterized by the absorption bands of the infrared spectrum described below:

4. The crystalline form of rimonabant monohydrate according to claim 1, characterized by the absorption bands of the infrared spectrum described below: λ (cm ^-1 ) = 3637, 3385, 1658, 1554, 1496.

5. The crystalline form of rimonabant monohydrate according to claim 1, characterized by the lines of the X-ray powder diffractograms described below:

6. The crystalline form of rimonabant monohydrate according to claim 1, characterized by the mesh parameters described below:

7. Process for the preparation of rimonabant monohydrate according to claim 1, characterized in that the rimonabant is dissolved in an organic solvent and water is added.

8. Process according to claim 7, characterized in that: a) a mixture of rimonabant is prepared in a solvent chosen from:

methylcyclohexane,

acetonitrile,

4-methyl-2-pentanone,

- acetone,

- toluene,

dimethylsulfoxide,

- or a mixture of these solvents; b) water is added dropwise.

9. Process according to claim 7, characterized in that: a) a saturated solution of rimonabant in a solvent chosen from:

methylcyclohexane,

acetonitrile,

4-methyl-2-pentanone,

- acetone,

- toluene,

dimethylsulfoxide,

10. Process according to claim 9, characterized in that: in step a), a solution of rimonabant in acetone is prepared, in step b), water is added dropwise so as to obtain an acetone / water mixture containing between 10 and 30% water by volume.

11. The method of claim 9 characterized in that: in step a), a solution containing between 150 and 200 g / 1 of rimonabant in acetone is prepared.

12. Process according to claim 7 for the preparation of the crystalline form of rimonabant monohydrate, characterized in that: a) a mixture of rimonabant is prepared in a solvent chosen from:

methylcyclohexane,

acetonitrile,

4-methyl-2-pentanone, acetone,

- toluene,

dimethylsulfoxide,

- or a mixture of these solvents; b) adding water dropwise; c) is cooled to a temperature between 0 ° and 15 ^° C.

13. The method of claim 12 characterized in that: a) is prepared at room temperature saturated solution of rimonabant in a solvent selected from:

methylcyclohexane, acetonitrile,

4-methyl-2-pentanone,

- acetone,

- toluene,

dimethylsulfoxide, or a mixture of these solvents; b) adding water dropwise; c) cooling between 0 ° C and 15 ° C; d) the crystals formed are filtered.

14. The method of claim 12 characterized in that in step a) is prepared at room temperature saturated solution of rimonabant in acetone.

15. The method of claim 12 characterized in that in step a) is prepared at room temperature a mixture containing between 150 and 200 g / 1 of rimonabant in acetone; in step b) is added dropwise between 10% and 30% water by volume.