MX2008010203A - Rimonabant monohydrate, process for the preparation thereof and pharmaceutical compositions containing same - Google Patents

Abstract

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

Description

RIMONABANT MONOHYDRATE. YOUR PROCEDURE PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT THEY CONTAIN The subject of the present invention is rimonabant monohydrate, its preparation method and pharmaceutical compositions containing it. Rimonabant is the international common name (INN) of 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 the international patent application WO2003 / 040105. A particular solvate has now been found: rimonabant monohydrate which has advantageous properties. By rimonabant monohydrate is meant the chemical compound consisting of a rimonabant molecule and a water molecule. The rimonabant monohydrate preferably exists in crystallized form. The present invention relates to rimonabant monohydrate, and more particularly to a crystalline form of rimonabant monohydrate. Obtaining a rimonabant solvate with a water molecule is particularly advantageous because the rimonabant monohydrate constitutes an active principle administrable to humans. The crystalline form of the rimonabant monohydrate constitutes a powder whose characteristics are improved with respect to the powders constituted either by the crystalline form I of the rimonabant or by the crystalline form I I of the rimonabant. Thus, when rimonabant monohydrate crystals are isolated by filtration from the solution in which they are formed, a better filterability is observed surprisingly than when it comes to filtering form I crystals or form II crystals from rimonabant . The improvement in filterability makes it possible to shorten the filtration step and involves an improvement in the texture of the filter cake which is characterized by a low humidity of the powder before drying and a low proportion of residual solvent before drying. The resulting powder after drying exhibits improved physical properties, mainly in terms of pourability and thus manipulability. The improvement of the filterability is measured by the study of the characteristics of the filter cake: for the rimonabant monohydrate in crystalline form, it is observed that it presents a specific resistance lower than that measured for the crystalline form I and for the crystalline form II of the rimonabant. The castability of the crystalline form of rimonabant monohydrate has been measured and compared to that of the crystalline form I I of rimonabant. The castability of crystalline forms is measured by the index of castability or compressibility index or Carr index as described in RL Carr: Evaluation of flow properties of solids, Chem. Eng., 1965, 163-168 as well as in the European pharmacopoeia. The index of castability is calculated according to the following relation: IC = 100 x (pt - pb) / pt where pt is the compressed density and pb the gross density. It is considered that this index is good if it is less than 20. The densities are determined experimentally by compressing the product in a graduated cylinder according to the mode of operation described in the European pharmacopoeia. The densities are determined after 10, 500, 1250 and 2500 strokes. The Carr index is determined from the measured data at 10 and 1250 strokes. A Carr index less than or equal to 20% is considered to correspond to a good fluence of the powders, while a Carr index greater than 21% is considered to correspond to an acceptable fluence of the powders, see difficult or very difficult. For the crystalline form of the rimonabant monohydrate, a Carr index equal to 20% is measured, that is, good, while for the crystalline form II of rimonabant, a Carr index of the order of 38% is measured, that is, very difficult . The Carr index measured for crystalline form I of rimonabant also corresponds to a very difficult collability. The good index of castability of the crystalline form of rimonabant monohydrate indicates that this form can easily be mixed with excipients during the preparation of pharmaceutical compositions for administration of rimonabant monohydrate. In particular, during the preparation of tablets, the fluence of the powder is improved and the content of active principle is better controlled. Thanks to the improved castability, the tablet manufacturing process can be simplified by eliminating certain stages such as wet granulation, drying and sizing, which increases the cadences and reduces the production cost. The present invention also relates to the process for obtaining rimonabant monohydrate. This process is characterized in that the rimonabant is dissolved 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 selected from: methylcyclohexane, acetonitrile, 4-methyl-2-pentanone, -acetone, toluene dimethyl sulfoxide or a mixture of these solvents; and b) water is added drop by drop. More particularly, in step a) a solvent selected from methylcyclohexane, acetonitrile, 4-methyl-2-pentanone, acetone, or a mixture of these solvents is used; Preferably, according to the process of the invention, step a) is carried out at room temperature. In particular, the process for the preparation of the rimonabant monohydrate according to the invention is characterized in that: a) for a saturated solution of rimonabant in a solvent selected from: methylcyclohexane, -acetonitrile, 4-methyl-2-pentanone, acetone, toluene, dimethyl sulfoxide, or a mixture of these solvents; b) water is added drop by drop; c) the rimonabant monohydrate formed is isolated. More particularly, in step a) a solvent chosen from: methyl-methylcyclohexane, acetonitrile, 4-methyl-2-pentanone, acetone, or a mixture of these solvents is used; 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 drop by drop so as to obtain a mixture of acetone / water containing between 10 and 30% water by volume; preferably, the mixture contains 20% water. A process for obtaining the rimonabant monohydrate in crystalline form is characterized in that: a) a mixture of rimonabant is prepared in a solvent selected from: methylcyclohexane, acetonitrile, 4-methyl-2-pentanone, -acetone, toluene dimethylsulfoxide or a mixture of these solvents; b) water is added drop by drop; c) it is cooled between 0 ° C and 1 5 ° C; and d) the crystals formed are filtered. More particularly, in step a) a solvent chosen from: methylcyclohexane, acetonitrile, 4-methyl-2-pentanone, acetone, or a mixture of these solvents is used; In particular, the process for the preparation of rimonabant monohydrate in crystalline form is characterized in that: a) a saturated solution of rimonabant is prepared at room temperature in a solvent selected from: methylcyclohexane, acetonitrile, 4-methyl-2-pentanone , acetone, toluene, dimethylsulfoxide, or a mixture of these solvents; b) water is added drop by drop; c) it is cooled between 0 ° C and 1 5 ° C; d) the crystals formed are filtered. More particularly, in step a) a solvent chosen from: methyl-methylcyclohexane, acetonitrile, 4-methyl-2-pentanone, acetone, or a mixture of these solvents is used; 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 1 50 and 200 g / l of rimonabant in acetone, preferably 200 g / l, is prepared at room temperature; b) 10% to 30% water by volume, preferably 20% water by volume, are added dropwise; c) is cooled to a temperature between 0 ° C and ° C, preferably 5 ° C; and d) the crystals formed are filtered. After step a), the formed mixture can be filtered in order to obtain a clear saturated solution. After filtering the last stage, the product obtained is dried at a temperature between room temperature and 40 ° C, preferably at room temperature. Preferably, the di solvent used in step a) of the process of the invention is acetone, which leads to isolating the rimonabant monohydrate from an acetone / water mixture, this mixture having conductive properties and its use makes it possible to avoid accumulation of dangerous electrostatic charges in the industrial plane. The rimonabant monohydrate is characterized by different elements of its physico-chemical analysis. Water content: The rimonabant monohydrate is characterized by elemental analysis and by the analysis of its water content measured in a Karl Fisher apparatus. Elemental analysis: C22 H23O2 N4CI 3 The theoretical and measured values take into account the presence of a mol ecula of water. Measured water content: 3.7% ± 0.5%; calculated: 3, 74%. The water content identifies the presence of the equivalent of one molecule of water per product molecule. Thermogravimetry: Thermogravimetric analysis was performed for rimonabant monohydrate in a TGA 2950 thermogravimetric analysis apparatus, marketed by TA Instruments SARL (PARIS, France); work under a nitrogen atmosphere, the initial temperature is 30 ° C, increases at a speed of 10 ° C / minute until the decomposition of the product. The theoretical weight loss corresponds to one mole of water is 3.74%. Experimentally by thermogravimetric analysis, it is equal to 3.55%. This result is in accordance with the theory and confirms that the product tested contains a water molecule that starts in the same temperature zone as for the differential enthalpy analysis, namely between 40 ° C and 100 ° C (Figure 1). The weight loss curve by thermogravimetry indicates that the water molecule has a hydration molecule. The crystalline form of rimonabant monohydrate has also been analyzed and characterized. Differential enthalpy analysis (in English: DSC = Differential Sean ni ng Calorimetry): The differential enthalpy analysis of the crystalline form of rimonabant monohydrate is carried out under the same conditions in an MDSC 2920 differential enthalpy analysis device, marketed by TA Instruments SARL ( Paris France); it is worked in a nitrogen atmosphere, the initial temperature is 30 ° C, it increases at a speed of 10 ° C / minute. It is compared with the results obtained in the same conditions for the crystalline form I I of rimonabant. For each compound, the melting peak and the enthalpy difference of the substance (??) before and after fusion are measured in Joules per gram of matter. According to Figure 2, the crystalline form I I has a melting peak at 157 + 2 ° C with ?? = 66 + 2 J / g. According to Figure 3, the crystalline form of rimonabant monohydrate loses its water molecule of crystallization between 40 ° C and 100 ° C. Simultaneously presents a melting peak located between 95 ° C + 5 ° C and 1 15 ° C + 5 ° C. The analysis of the water vapor sorption / desorption measurement is performed on the crystalline form of the rimonabant monohydrate in an SGA100 analysis apparatus marketed by VTI (USA). Work between 0% and 100% relative humidity at 25 ° C after degassing the monohydrated form at 80 ° C for 3 hours. The rimonabant monohydrate loses its hydration water molecule in the course of drying at 80 ° C. In the course of the water vapor sorption cycle, the transformation of rimonabant into rimonabant monohydrate is produced from 40% relative humidity. The sorption / desorption isotherm is depicted in Figure 4. According to the present invention, the crystalline form of rimonabant monohydrate is also characterized by its infra-red spectrum (R. R.). This is compared with that of the crystalline form II of the rimonabant described above. The infra-red spectra (I R.) of these 2 crystalline forms of the monabant ri are recorded in Perkin Elmer System 2000 FT-I R spectrophotometers, between 400 crrf1 and 4000 cm "1, with a resolution of 4 cm'1, in a potassium bromide tablet, the compound being tested at a concentration of 0.5% by weight These spectra are characterized by the absorption bands described in the following Tables 1 and 2. Table 1 IR Spectrum Crystalline Form Rimonabant Monohydrate Table 2: Spectrum I.R .. Crystal Form II Rimonabant The large band observed from 3637 to 3208 cm'1 in the IR spectrum of the crystalline form of rimonabant monohydrate (Figure 5) corresponds to the vibration of the HOH bonds of the hydrate constitutes one of the characteristics of said spectrum I R. For the rest of IR spectra, comparing Figures 5 and 6 where they are represented, slight differences are observed in the level of the positions and / or intensities of the rays, but the 2 spectra present the same general appearance. Thus, the IR spectrum of the crystalline form of rimonabant monohydrate is characterized by the following absorption bands:? (cm 1) = 3637; 3385; 1658; 1554; 1496; 990; 780 and more particularly by the bands? = 3637 cm "1; 3385 cm" 1; 1658 cm "1; 1 554 cm '1 and 1496 cm" 1. The crystalline form of rimonabant monohydrate is also characterized by the characteristic stripes of the powder X-ray diffractogram. The powder X-ray diffraction (RX) profile (diffraction angle) is established with a Siemens D500TT diffractometer (theta / theta), of the Bragg-Brentano type; CuKci source! ,? = 1 .5406Á; Scan domain 2 ° to 40 ° to 1 ° per minute at 2 Bragg theta angle.

The characteristic lines of the diffractogram are shown in Table 3 below: Table 3 X-Rays on Powder. Crystalline Form of Rimonabant Monohydrate Under the same conditions, the characteristic lines of the X-ray diffractogram are recorded on powder of the crystalline form I I of the rimonabant, the characteristic lines being recorded in Table 4 below: Table 4 X-Rays on Powder. Crystal Form Rimonabant li The corresponding diffractograms are reproduced in the Figures 7 and 8. The crystalline form of rimonabant monohydrate is also characterized by its crystalline structure for which the parameters of the unit cells were determined by X-ray diffraction on single crystal. Table 5 Cell Parameters Unit Pe The Crystalline Form of Rimonabant Monohydrate The values () in the column on the right correspond to the standard deviations observed for this measure. In Figure 9, the theoretical and experimental diffractograms of rimonabant monohydrate are compared by superposition. From the parameters of the unit cell and the atomic coordinates x, y, z of the atoms of the molecule, computerized calculation programs allow us to plot perspective views of the crystalline unit cell of the molecule i. As seen from Figure 10, this representation of the molecule in the crystalline unit cell reveals the presence of the water molecule that participates well in the crystalline building (water of crystallization). Example: Preparation of the crystalline form of rimonabant monohydrate. 80 g of rimonabant of the form I I are suspended in 400 ml of acetone at room temperature under stirring overnight. The suspension is filtered so that a solution of rimonabant in saturated and clear acetone is obtained. 100 ml of water are introduced into this solution, which causes the progressive insolubilizactón 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 whose water content is 3.4%, which is in accordance with the theoretical water content (3.7%). The title of rimonabant of the obtained compound is 96.6%. Thus, it seems that no impurity is quantifiable in the compound obtained. The X-ray diagram of dust is shown in Figure 11.

Claims (10)

1. CLAIMING IS 1. The rimonabant monohydrate.
2. 2. The crystal form of the rimonabant monohydrate according to claim 1, characterized by a melting peak between 95 ° C + 5 ° C and 1 15 ° C + 5 ° C.
3. 3. The crystalline form of the rimonabant monohydrate according to claim 1, characterized by the infra-red spectrum absorption bands described below:
4. 4. The crystalline form of the rimonabant monohydrate according to claim 1, characterized by the absorption bands of infra-red spectrum described below:? (cm 1) = 3637; 3385; 1658; 1554; 1496.
5. 5. The crystalline form of rimonabant monohydrate according to claim 1, characterized by the X-ray powder diffractogram stripes described below:
6. 6. The crystalline form of the rimonabant monohydrate according to claim 1, characterized by the unit cell parameters described below:
7. 7. Preparation process rimonabant monohydrate according to claim 1, characterized in that the rimonabant is dissolved in an organic solvent and water is added. Process according to claim 7, characterized in that: a) a mixture of rimonabant is prepared in a solvent selected from: methylcyclohexane, acetonitrile, 4-methyl-2-pentanone, acetone, -toluene dimethylsulfoxide or a mixture of these solvents; b) Water is added drop by drop. 9. Process according to claim 7, characterized in that: a) a saturated solution of rimonabant is prepared at room temperature in a solvent selected from: methylcyclohexane, acetonitrile, 4-methyl-2-pentanone, acetone, toluene, dimethylsulfoxide, or a mixture of these solvents; b) water is added drop by drop; c) the rimonabant monohydrate formed is isolated. 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 that an acetone / water mixture containing between 10 and 30% of water by volume. eleven . Process according to claim 9, characterized in that: in step a), a solution containing between 150 and 200 g / l of rimonabant in acetone is prepared. Process according to claim 7 for preparing the crystalline form of rimonabant monohydrate, characterized in that: a) a mixture of rimonabant is prepared in a solvent selected from: methylcyclohexane, acetonitrile, 4-methyl-2-pentanone, acetone, toluene, di methylsulfoxide, or a mixture of these solvents; b) water is added drop by drop; c) is cooled to a temperature between 0o and 1 5 ° C. The process according to claim 12, characterized in that: a) a saturated solution of ri monabant is prepared at room temperature in a solvent selected from: methylcyclohexane, acetonitrile, 4-methyl-2-pentanone, -acetone, toluene, dimethylsulfoxide, or a mixture of estoa solvents; b) water is added drop by drop; c) it is cooled between 0 ° C and 1 5 ° C; d) the crystals formed are filtered. 14. Process according to claim 12, characterized in that in step a) a saturated solution of rimonabant in acetone is prepared at room temperature. 15. Process according to claim 1 2, characterized in that in step a), a solution containing between 150 and 200 g / l of rimonabant in acetone is prepared at room temperature; in step b), between 10% and 30% water by volume is added dropwise.