Abstract:
The present invention discloses a process for the preparation of atomoxetine hydrochloride in a pure crystalline form, characterised by an XRPD spectrum as in FIG.  1 . It is also object of the present invention to provide methods to obtain pure atomoxetine hydrochloride without the use of methylene chloride.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention provides crystalline atomoxetine hydrochloride and methods for its preparation by means of safe crystallization conditions and avoiding the use of halogenated solvents. 
       BACKGROUND OF THE INVENTION 
       [0002]    Atomoxetine hydrochloride or (R)—N-methyl-γ-(2-methylphenoxy)-benzenepropanamine hydrochloride has been used as a medicament in the treatment of attention deficit disorders. The X-ray powder diffraction data of atomoxetine hydrochloride have been reported into ICDD database (International Centre Diffraction Data) by Ely Lilly since 1987. According to EP 0052492, crystallization of Atomoxetine is performed in methylene chloride/ethyl acetate mixtures. However, halogenated solvents are harmful, and their use is questioned due to their potential environmental impact. In addition, being the crystallization the last step in the manufacture, methylene chloride traces are likely to be retained in the final product. It is therefore important to substitute halogenated solvents with more suitable ones, from the point of view of the industrial production, environmental impact, and purity of the final product. 
         [0003]    It has now been found that crystallization of atomoxetine can be advantageously carried out with different solvent mixtures without methylene chloride. 
         [0004]    Crystalline form of atomoxetine, characterised by an X-ray powder diffraction pattern having a number of additional, significant peaks, that were not present in the spectrum reported in the database, have also been obtained and are a further object of the invention. 
         [0005]    A preferred crystalline nature of the present invention is of monocrystalline form and is characterised by crystal size in the range up to millimeter. 
         [0006]    One of said crystals was analysed by single crystal X-ray diffraction. 
         [0007]    The study has led to the determination of the molecular and crystalline structure of atomoxetine hydrochloride. The X-ray structure clearly shows that the crystalline material is atomoxetine hydrochloride. To test the crystalline homogeneity of the product, the above sample was subjected, after accurate milling, to X-ray powder diffraction (“XRPD”). The obtained spectrum was compared with the theoretical X-ray powder diffraction spectrum, calculated from the geometrical data of the single crystal X-ray analysis. Necessarily, the calculated diffractogram contains all and exclusively only the diffraction peaks of the pure substance. The two diffractograms, the experimental one and the calculated one, are superimposable, showing the same angular sequence of the diffraction peaks and relative intensities of the corresponding peaks very similar. Some differences observed in the peak intensities can be imputed to “preferred orientation” effect, typically arising from crystalline morphology and/or analytical sample preparation. 
         [0008]    This test shows the homogeneity of the sample and the crystalline purity of the product. 
         [0009]    It has now been surprisingly found that the XRPD spectrum of the atomoxetine HCl obtained as here described, shows a number of additional and significant diffraction peaks with respect to the one reported in ICDD (International Centre Diffraction Data) by Ely Lilly in 1987, that appears therefore to be approximate or incomplete. 
       SUMMARY OF THE INVENTION 
       [0010]    It is therefore an object of the present invention a process for the preparation of atomoxetine hydrochloride in a pure crystalline form, characterised by an XRPD spectrum as in  FIG. 1 . It is also object of the present invention to provide methods to obtain pure atomoxetine hydrochloride without the use of methylene chloride. 
         [0011]    In addition, the invention refers to atomoxetine hydrochloride having an X-ray powder diffraction pattern different than that reported in ICDD (International Centre Diffraction Data) by Ely Lilly in 1987. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0012]      FIG. 1  shows the X-ray powder diffractogram of crystalline atomoxetine hydrochloride. 
           [0013]      FIG. 2  shows the theoretical X-ray powder diffractogram calculated from the single crystal X-ray data. 
           [0014]      FIG. 3  shows the thermogram obtained by differential scanning calorimetry. 
           [0015]      FIG. 4  shows the molecular structure of the atomoxetine hydrochloride, with the atom-numbering scheme. 
           [0016]      FIG. 5  shows a packing diagram of the compound, viewed along the b axis 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0017]    The present invention provides a crystalline form of Atomoxetine hydrochloride, at least 95% pure, obtainable without using methylene chloride as solvent. 
         [0018]    The characterization of the crystalline pure form by X-ray powder and single crystal x-ray diffraction is reported. 
         [0019]    Accordingly, the present invention provides atomoxetine hydrochloride crystalline form having a typical X-ray powder diffraction pattern (“XRPD”) of  FIG. 1 . The crystalline form is also characterized by lattice spacings (d values) and relative intensities of its X-ray powder pattern as reported in table 1. The XRPD pattern has been collected using CuKα (λ=1.5418 Å) radiation, with a step width of 0.04°. 
         [0020]    The crystalline form is also characterized by having the following crystal cell parameters: a=7.355(1)Å, b=13.325(1)Å, c=16.680(2)Å, Orthorhombic System, space group P2 1 2 1 2 1 , and the atomic coordinates of the molecule as reported in Table 2 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 List of the most prominent peaks of the X-ray powder 
               
               
                 diffraction pattern of Atomoxetine Hydroclhoride 
               
             
          
           
               
                 Nr. # 
                 2-theta (deg) 
                 d (Å) 
                 Intensity (cps) 
                 I/Imax (%) 
               
               
                   
               
             
          
           
               
                 1 
                 8.48 
                 10.419 
                 139 
                 23 
               
               
                 2 
                 10.60 
                 8.339 
                 51 
                 8 
               
               
                 3 
                 12.52 
                 7.064 
                 37 
                 6 
               
               
                 4 
                 13.24 
                 6.682 
                 73 
                 12 
               
               
                 5 
                 13.72 
                 6.449 
                 247 
                 41 
               
               
                 6 
                 14.28 
                 6.197 
                 56 
                 9 
               
               
                 7 
                 14.72 
                 6.013 
                 321 
                 53 
               
               
                 8 
                 16.04 
                 5.521 
                 86 
                 14 
               
               
                 9 
                 17.36 
                 5.104 
                 605 
                 100 
               
               
                 10 
                 17.92 
                 4.946 
                 119 
                 20 
               
               
                 11 
                 18.72 
                 4.736 
                 577 
                 95 
               
               
                 12 
                 20.00 
                 4.436 
                 70 
                 12 
               
               
                 13 
                 20.68 
                 4.292 
                 137 
                 23 
               
               
                 14 
                 20.88 
                 4.251 
                 183 
                 30 
               
               
                 15 
                 21.08 
                 4.211 
                 600 
                 99 
               
               
                 16 
                 22.28 
                 3.987 
                 123 
                 20 
               
               
                 17 
                 22.64 
                 3.924 
                 349 
                 58 
               
               
                 18 
                 23.36 
                 3.805 
                 43 
                 7 
               
               
                 19 
                 24.08 
                 3.693 
                 313 
                 52 
               
               
                 20 
                 24.52 
                 3.628 
                 48 
                 8 
               
               
                 21 
                 24.76 
                 3.593 
                 73 
                 12 
               
               
                 22 
                 25.08 
                 3.548 
                 103 
                 17 
               
               
                 23 
                 25.40 
                 3.504 
                 111 
                 18 
               
               
                 24 
                 25.68 
                 3.466 
                 114 
                 19 
               
               
                 25 
                 26.44 
                 3.368 
                 110 
                 18 
               
               
                 26 
                 26.74 
                 3.331 
                 39 
                 6 
               
               
                 27 
                 27.28 
                 3.266 
                 427 
                 71 
               
               
                 28 
                 27.68 
                 3.220 
                 45 
                 7 
               
               
                 29 
                 27.96 
                 3.189 
                 79 
                 13 
               
               
                 30 
                 28.40 
                 3.140 
                 174 
                 29 
               
               
                 31 
                 28.84 
                 3.093 
                 42 
                 7 
               
               
                 32 
                 29.08 
                 3.068 
                 56 
                 9 
               
               
                 33 
                 29.36 
                 3.040 
                 249 
                 41 
               
               
                 34 
                 29.84 
                 2.992 
                 157 
                 26 
               
               
                 35 
                 30.12 
                 2.965 
                 68 
                 11 
               
               
                 36 
                 31.28 
                 2.857 
                 54 
                 9 
               
               
                 37 
                 31.80 
                 2.812 
                 53 
                 9 
               
               
                 38 
                 32.00 
                 2.795 
                 91 
                 15 
               
               
                 39 
                 32.40 
                 2.761 
                 54 
                 9 
               
               
                 40 
                 33.32 
                 2.687 
                 35 
                 6 
               
               
                 41 
                 33.60 
                 2.665 
                 53 
                 9 
               
               
                 42 
                 35.12 
                 2.553 
                 67 
                 11 
               
               
                 43 
                 35.52 
                 2.525 
                 46 
                 8 
               
               
                 44 
                 35.80 
                 2.506 
                 28 
                 5 
               
               
                 45 
                 36.20 
                 2.479 
                 33 
                 5 
               
               
                 46 
                 36.72 
                 2.446 
                 29 
                 5 
               
               
                 47 
                 38.36 
                 2.345 
                 42 
                 7 
               
               
                 48 
                 38.80 
                 2.319 
                 48 
                 8 
               
               
                 49 
                 39.40 
                 2.285 
                 43 
                 7 
               
               
                 50 
                 39.92 
                 2.257 
                 32 
                 5 
               
               
                 51 
                 40.16 
                 2.244 
                 35 
                 6 
               
               
                 52 
                 40.28 
                 2.237 
                 39 
                 6 
               
               
                 53 
                 40.60 
                 2.220 
                 52 
                 9 
               
               
                 54 
                 42.00 
                 2.149 
                 55 
                 9 
               
               
                 55 
                 42.16 
                 2.142 
                 44 
                 7 
               
               
                 56 
                 42.44 
                 2.128 
                 45 
                 7 
               
               
                 57 
                 42.52 
                 2.124 
                 31 
                 5 
               
               
                 58 
                 43.28 
                 2.089 
                 29 
                 5 
               
               
                 59 
                 43.88 
                 2.062 
                 28 
                 5 
               
               
                 60 
                 44.68 
                 2.027 
                 40 
                 7 
               
               
                 61 
                 44.84 
                 2.020 
                 48 
                 8 
               
               
                 62 
                 45.60 
                 1.988 
                 39 
                 6 
               
               
                 63 
                 47.92 
                 1.897 
                 70 
                 12 
               
               
                 64 
                 48.12 
                 1.889 
                 36 
                 6 
               
               
                 65 
                 49.24 
                 1.849 
                 33 
                 5 
               
               
                 66 
                 49.50 
                 1.840 
                 29 
                 5 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Fractional atomic coordinates of Atomoxetine hydroclhoride 
               
               
                 (×10 4 ), with equivalent isotropic displacement parameters (Å 2 ) 
               
             
          
           
               
                 Atom 
                   
                 x 
                 y 
                 z 
                 Ueq 
               
               
                   
               
             
          
           
               
                 Cl (1)  
                 11583 
                 (1) 
                 3248 
                 (1) 
                 4389 (1) 
                 54 (1) 
               
               
                 O (1) 
                 2935 
                 (3) 
                 2477 
                 (1) 
                 7552 (1) 
                 49 (1) 
               
               
                 N (1) 
                 474 
                 (3) 
                 1175 
                 (2) 
                 5133 (1) 
                 44 (1) 
               
               
                 C (1) 
                 2961 
                 (4) 
                 1538 
                 (2) 
                 7128 (1) 
                 40 (1) 
               
               
                 C (2) 
                 1792 
                 (4) 
                 1762 
                 (2) 
                 6395 (1) 
                 44 (1) 
               
               
                 C (3) 
                 1705 
                 (4) 
                 908 
                 (2) 
                 5802 (1) 
                 42 (1) 
               
               
                 C (4) 
                 107 
                 (5) 
                 324 
                 (3) 
                 4579 (2) 
                 62 (1) 
               
               
                 C (5) 
                 2209 
                 (4) 
                 702 
                 (2) 
                 7634 (1) 
                 40 (1) 
               
               
                 C (6) 
                 2859 
                 (4) 
                 −267 
                 (2) 
                 7559 (2) 
                 51 (1) 
               
               
                 C (7) 
                 2139 
                 (6) 
                 −1042 
                 (2) 
                 8007 (2) 
                 68 (1) 
               
               
                 C (8) 
                 781 
                 (6) 
                 −859 
                 (2) 
                 8546 (2) 
                 70 (1) 
               
               
                 C (9) 
                 110 
                 (5) 
                 86 
                 (3) 
                 8622 (2) 
                 68 (1) 
               
               
                 C (10)  
                 805 
                 (4) 
                 874 
                 (2) 
                 8168 (2) 
                 54 (1) 
               
               
                 C (11)  
                 4053 
                 (4) 
                 2616 
                 (2) 
                 8205 (1) 
                 43 (1) 
               
               
                 C (12)  
                 3667 
                 (4) 
                 3490 
                 (2) 
                 8639 (1) 
                 49 (1) 
               
               
                 C (13)  
                 4764 
                 (5) 
                 3703 
                 (2) 
                 9292 (2) 
                 63 (1) 
               
               
                 C (14)  
                 6169 
                 (6) 
                 3084 
                 (3) 
                 9516 (2) 
                 70 (1) 
               
               
                 C (15)  
                 6525 
                 (5) 
                 2238 
                 (3) 
                 9078 (2) 
                 71 (1) 
               
               
                 C (16)  
                 5471 
                 (5) 
                 1996 
                 (2) 
                 8418 (2) 
                 58 (1) 
               
               
                 C (17)  
                 2149 
                 (6) 
                 4155 
                 (3) 
                 8394 (2) 
                 79 (1) 
               
               
                   
               
             
          
         
       
     
         [0021]    The invention also provides a process for the preparation of the above described pure crystalline form of atomoxetine hydrochloride as crystalline powder, which comprises:
       i) Dissolving crude Atomoxetine hydrochloride obtained by a known method in a suitable solvent, at a suitable temperature,   ii) Cooling the solution to a suitable temperature for a suitable time,   iii) Filtering the obtained suspension,   iv) Drying the collected crystals under vacuum, and   v) Optionally milling or micronizing the obtained crystals, to obtain a particle size suitable for the pharmaceutical manufacturing,       
 
         [0027]    Suitable solvents for step i) include C 1 -C 4  alcohols, such as methanol, ethanol, propanol, iso-propanol, n-butanol, sec-butyl alcohol or t-butanol; C 1 -C 4  esters of organic C 2 -C 4  acids, such as ethyl acetate, methyl acetate, ethyl propionate and the like; aliphatic or aromatic hydrocarbons, such as hexanes, petroleum ethers, heptanes, toluene, or xylenes and the like; ethers, such as tetrahydrofuran, dioxane, diethyl ether; water or mixtures thereof. 
         [0028]    Preferred solvents are C 1 -C 3  alcohols such as methanol, ethanol, or iso-propanol; C 1 -C 4  esters of organic C 2 -C 4  acids, such as ethyl acetate; aromatic hydrocarbons, such as toluene; ethers, like tetrahydrofuran; and water. Most preferred solvents include methanol, ethanol, iso-propanol, toluene, tetrahydrofuran, ethyl acetate and water or mixtures thereof. 
         [0029]    Suitable temperatures for step i) range from 20° C. to 200° C., preferably from 20° C. to 150° C. The solvent reflux temperature is particularly preferred. 
         [0030]    Suitable temperatures for step ii) range from −20° C. to 40° C., preferably from 0° C. to 30° C., and most preferred temperatures range from 0 to 25° C. Suitable time for step ii) ranges from overnight to several days, preferably from overnight to four days, and most preferably from one to three days. 
         [0031]    Another object of the invention is a process for the preparation of pure atomoxetine hydrochloride in form of monocrystals of millimetric dimensions, which comprises:
       i) Dissolving a crude Atomoxetine hydrochloride in a suitable solvent, at a suitable temperature;   ii) Letting the solution stand for a suitable time at 0-25° C.;   iii) Filtering the obtained crystals;   iv) Drying under vacuum the collected crystals;       
 
         [0036]    Preferred solvents for step i) include ethanol/ethyl acetate mixtures, or water. Suitable temperatures include temperatures ranging from 20° C. to 200° C., preferably from 20° C. to 150° C., The solvent reflux temperature is particularly preferred. 
         [0037]    The solution is left to stand in step ii) at 0-25° C. until the formation of well defined and separated crystals of the desired dimensions is obtained. This time depends on the temperature used. 
         [0038]    In order to obtain a particle size suitable for the pharmaceutical manufacturing, the crystalline Atomoxetine hydrochloride obtained with the previous method, were optionally submitted to milling or micronizing 
         [0039]    The composition containing said crystalline form may be in a form suitable for oral dosage as a tablet, capsule, suspension, ointment, lotion. These formulations may contain additional additives, such as sweetening or flavouring agents, coating and inert diluents, such as lactose and talc, binders and suspending agents, such as starch, hydroxyethylcellulose, hydroxypropyl cellulose and the like. Any conventional technique may be used for the preparation of pharmaceutical formulations according to the invention. 
         [0040]    The invention is illustrated in more detail in the following examples. 
       EXAMPLE 1 
       [0041]    Atomoxetine hydrochloride (7 g) was dissolved in ethanol/ethyl acetate at about 70-80° C. Part of the solvent was then distilled off until precipitation began. Additional ethyl acetate was then added maintaining the temperature at about 60° C. until precipitation was complete. The suspension was then cooled at 0-5° C., and let standing overnight. The suspension was filtered and the solid washed with ethyl acetate, collected and dried under vacuum. Atomoxetine hydrochloride was obtained as white crystals. 
         [0042]    A crystal having approximate dimension of about 0.4×0.5×0.6 mm, was selected, mounted on a glass fibre and subjected to single crystal X-ray diffraction. Unit cell parameters were determined using 74 reflections in the range 11.4≦2θ≦86°. The atomoxetine hydrochloride was found to crystallise in the Orthorhombic System, space group P2 1 2 1 2 1 , unit cell dimensions: a=7.355(1)Å, b=13.325(1)Å, c=16.680(1)Å, V=1634.6(3) Å 3 . Intensities data were collected on a Siemens P4 diffractometer, at room temperature, using graphite monochromated Cu—Kα radiation (λ=1.54179 Å), and θ/2θ scan technique. A total of 2866 reflections (2404 unique, R int =0.056) were collected up to 130° in 2θ, with index range: −8≦h≧7, −15≦k≧15, −19≦1≧19. 
         [0043]    The structure was solved by direct methods using SIR97 program (A. Altomare et al.: SIR97: A New Tool for Crystal Structure Determination and Refinement.  J. Appl. Cryst.  1999, 32, 115-119) and refined by full-matrix least-squares procedure with SHELXL97 (G. M. Sheldrick. SHELXL-97. Program for the Refinement of Crystal Structures. 1997. University of Göttingen, Germany), with anisotropic temperature factors for non-H atoms. The final stage of refinement converged to R=0.0481 for 2354 observed reflections, with I≧2σ(I), and 210 refined parameters. 
         [0044]    The (R) absolute stereochemistry of the chiral centre of the molecule was confirmed by the Flack parameter (x parameters=0.04(2)), on the basis of 822 Friedel pairs. 
       EXAMPLE 2 
       [0045]    Atomoxetine hydrochloride (3 g) was suspended in water (25 ml), and the suspension heated until dissolution. The solution was then cooled to 15-25° C., and stirred for 72 hours. The obtained suspension was then filtered. The solid was collected and dried under vacuum to yield crystalline atomoxetine hydrochloride having an XRPD spectrum as shown in  FIG. 1 . 
       EXAMPLE 3 
       [0046]    Atomoxetine hydrochloride (3 g) was suspended in toluene and the suspension heated until dissolution. The solution was then cooled to 15-25° C. and stirred for 72 hours. The obtained suspension was then filtered. The solid was collected and dried under vacuum to yield atomoxetine hydrochloride with the same crystalline phase of example 2. 
       EXAMPLE 4 
       [0047]    Atomoxetine hydrochloride (3 g) was suspended in isopropanol (50 ml), and the suspension was heated until dissolution. The solution was then cooled to 15-25° C. and stirred for 72 hours. The obtained suspension was then filtered. The solid was collected and dried under vacuum to yield atomoxetine hydrochloride with the same crystalline phase of example 2. 
       EXAMPLE 5 
       [0048]    Atomoxetine hydrochloride (3 g) was suspended in tetrahydrofuran (200 ml), and the suspension was heated until dissolution. The solution was then cooled to 15-25° C. and stirred for 72 hours. The obtained suspension was then filtered. The solid was collected and dried under vacuum to yield atomoxetine hydrochloride with the same crystalline phase of example 2. 
       EXAMPLE 6 
       [0049]    Atomoxetine hydrochloride (3 g) was dissolved in warm methanol (25 ml) until complete dissolution. The solvent was then allowed to evaporate until crystallization is complete. The obtained suspension was then filtered. The solid was collected and dried under vacuum to yield large crystals of atomoxetine hydrochloride, having the unit cell dimensions as in example 1.