Patent Document

[0001]    This invention refers to a novel crystal form of Aliskiren hemifumarate, having the novel distinctive physico-chemical properties described herein and also to a novel amorphous solid of the same Aliskiren hemifumarate. A further object of this invention is a process for the preparation of said forms of Aliskiren hemifumarate. 
       STATE OF THE ART 
       [0002]    Aliskiren is an anti-hypertension that acts on the renin-angiotensin-aldosterone system, inhibiting this. In particular, Aliskiren is a direct inhibitor of renin. Renin is the enzyme that, secreted by the juxtaglomerular apparatus of the kidneys following sympathetic stimulation caused by a drop in blood pressure, converts angiotensinogen (inactive protein produced by the liver and normally in circulation) into Angiotensin 1 which is then converted by the ACE (Angiotensin Converting Enzyme) into Angiotensin 2, an active protein with vascular constriction effects that stimulates the production of aldosterone. 
         [0003]    The chemical name of Aliskiren of formula (A) is (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxypropyl)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)pheny]methyl]-8-methyl-2-propan-2 ilnonanamide. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0004]    Known difficulties tied to the formulation of Aliskiren are to be ascribed principally to its highly hygroscopic nature and relatively low stability. 
         [0005]    The hemifumarate salt of Aliskiren is known and used in therapy. 
         [0006]    WO2009/064479 describes amorphous and polymorphic forms of Aliskiren hemifumarate and processes for their preparation. Crystal forms of Aliskiren hemifumarate are described in WO2008/061622. WO2009/143423 describes monofumarate Aliskiren and related preparation processes. The free base of Aliskiren is described in WO2009/149344. 
         [0007]    The physical properties of a solid state active principle are fundamental in managing the material during transformation into a pharmaceutical product. Emphasis is laid, in particular, on flowability properties in addition to speed of dissolution in an aqueous liquid. The latter will influence the speed of dissolution of the active principle in the stomach of a patient, with evident therapeutic consequences. Considerable attention must be paid to dissolution speed also in the formulation of syrups, tonics and other liquid medicaments. These and other physical characteristics are influenced by the shape and orientation of the molecules in a unit cell which defines a particular polymorphic form of a substance. The polymorphic form may result in different thermal behaviour from that of the amorphous materials or another polymeric form. Thermal behaviour is measured in the laboratory with techniques such as the capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and may be used to distinguish certain polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties, recordable through X-ray crystallography, NMR spectrometry and infrared spectrometry. 
         [0008]    The discovery of novel forms of Aliskiren hemifumarate provides an opportunity to improve the process of synthesis of the active pharmaceutical ingredient (API), generating a form of Aliskiren hemifumarate with improved characteristics, for example, in terms of flowability and solubility, currently lacking in the state of the art. 
         [0009]    A novel crystal form of Aliskiren hemifumarate, with distinctive, advantageous physico-chemical characteristics, is prepared, described and characterised here for the first time. 
       DESCRIPTION OF THE INVENTION 
       [0010]    The aim of this invention is to make available a novel crystal form and a novel amorphous solid of Aliskiren hemifumarate. 
         [0011]    More complete understanding of this invention can be obtained referring to the summary tables of certain physico-chemical characteristics of Aliskiren hemifumarate provided below. 
         [0012]    The main peaks of X-ray powder diffraction, the main bands and characteristic of the FT-IR spectrum, the thermogravimetric analysis are furnished. 
         [0013]    The X-ray powder diffractogram (XRPD) has been obtained using the instrument X&#39;Pert PRO PANalytical with single scan, using Kα1 radiation. The diffractogram is measured in reflection mode in the range 3-40° 2θ. 
         [0014]    The FT-IR spectrum (Fourier transform IR spectroscopy) was recorded with the Nicolet FT-IR 6700 (ThermoFischer) appliance equipped with a KBr splitter and DTGS KBr detector. The spectrum was acquired in 16 scans at a resolution of 4 cm −1  for the crystal form and the solvate, in 32 scans at a resolution of 4 cm −1  for the amorphous solid. 
         [0015]    DSC analyses were carried out using a differential scanning calorimeter DSC 200 F3 Maia®. The samples were loaded in an aluminium crucible and heated at 10° C./min in the temperature range from 20 to 450° C. 
         [0016]    The thermograms were obtained using the STA 409 PC Luxx® Netzsch thermo-balance. The samples were loaded in an aluminium crucible and heated at 10° C./min in the temperature range from 25 to 490° C. 
     
    
     
       DESCRIPTION OF THE FIGURES 
         [0017]      FIG. 1 : XRPD spectrum of Aliskiren hemifumarate, crystal form. 
           [0018]      FIG. 2 : FT-IR spectrum of Aliskiren hemifumarate, crystal form. 
           [0019]      FIG. 3 : DSC analysis of Aliskiren hemifumarate, crystal form. 
           [0020]      FIG. 4 : TGA analysis of Aliskiren hemifumarate, crystal form. 
           [0021]      FIG. 5 : XRPD spectrum of Aliskiren hemifumarate p-xylene solvate. 
           [0022]      FIG. 6 : FT-IR spectrum of Aliskiren hemifumarate p-xylene solvate. 
           [0023]      FIG. 7 : DSC analysis of Aliskiren hemifumarate p-xylene solvate. 
           [0024]      FIG. 8 : TGA analysis of Aliskiren hemifumarate p-xylene solvate. 
           [0025]      FIG. 9 : XRPD spectrum of Aliskiren hemifumarate, amorphous solid. 
           [0026]      FIG. 10 : FT-IR spectrum of Aliskiren hemifumarate, amorphous solid. 
           [0027]      FIG. 11 : DSC analysis of Aliskiren hemifumarate, amorphous solid. 
           [0028]      FIG. 12 : TGA analysis of Aliskiren hemifumarate, amorphous solid. 
           [0029]      FIG. 13 : dissolution speed of Aliskiren hemifumarate, amorphous solid (curve A) and Aliskiren hemifumarate, amorphous solid obtained as described in WO2008/061622 (curve B). 
           [0030]      FIG. 14 : XRPD spectrum of Aliskiren hemifumarate, amorphous solid obtained as described in WO2008/061622, before and after exposure for 5 days at 25° C., 60% RH. 
           [0031]      FIG. 15 : XRPD spectrum of Aliskiren hemifumarate, amorphous solid, before and after exposure for 5 days at 25° C., 60% RH. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0032]    The crystal form of Aliskiren hemifumarate claimed in this invention is preferably obtained through desolvation of Aliskiren hemifumarate solvate with p-xylene and is characterised by the following physico-chemical parameters. 
         [0033]    XRPD analysis makes it possible to obtain the characteristic spectrum shown in  FIG. 1 . Main peaks at 2theta+/−0.3 degrees are: 5.8, 5.9, 9.6, 10.8, 15.6, 16.4, 18.4, 18.9. Table 1 below shows the significant peaks of the spectrum. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                   
                   
                 FWHM 
                   
                   
               
               
                 Pos. [° 2Th.] 
                 Height [cts] 
                 [° 2Th.] 
                 d-spacing [Å] 
                 Rel. Int. [%] 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 5.7633 
                 597.73 
                 0.0836 
                 15.33488 
                 95.82 
               
               
                 5.8783 
                 597.72 
                 0.1004 
                 15.03525 
                 95.82 
               
               
                 7.5402 
                 114.81 
                 0.1673 
                 11.72475 
                 18.41 
               
               
                 9.5848 
                 356.92 
                 0.3011 
                 9.22775 
                 57.22 
               
               
                 10.8149 
                 623.79 
                 0.0836 
                 8.18080 
                 100.00 
               
               
                 11.8491 
                 103.35 
                 0.2342 
                 7.46899 
                 16.57 
               
               
                 13.3056 
                 61.00 
                 0.3346 
                 6.65444 
                 9.78 
               
               
                 14.1782 
                 76.24 
                 0.2676 
                 6.24684 
                 12.22 
               
               
                 15.6019 
                 257.52 
                 0.1673 
                 5.67986 
                 41.28 
               
               
                 16.4443 
                 429.99 
                 0.1004 
                 5.39074 
                 68.93 
               
               
                 18.4279 
                 383.83 
                 0.2007 
                 4.81471 
                 61.53 
               
               
                 18.8711 
                 229.28 
                 0.1673 
                 4.70262 
                 36.76 
               
               
                 19.8882 
                 42.40 
                 0.3346 
                 4.46436 
                 6.80 
               
               
                 20.5874 
                 132.29 
                 0.1338 
                 4.31429 
                 21.21 
               
               
                 20.9682 
                 178.71 
                 0.2676 
                 4.23679 
                 28.65 
               
               
                 21.9324 
                 188.48 
                 0.4684 
                 4.05266 
                 30.22 
               
               
                 23.9282 
                 63.15 
                 0.1673 
                 3.71896 
                 10.12 
               
               
                 25.0750 
                 114.37 
                 0.1673 
                 3.55142 
                 18.34 
               
               
                 26.2090 
                 22.66 
                 0.4015 
                 3.40027 
                 3.63 
               
               
                 27.2420 
                 67.56 
                 0.2342 
                 3.27364 
                 10.83 
               
               
                 28.3084 
                 18.87 
                 0.4015 
                 3.15270 
                 3.02 
               
               
                 29.4345 
                 24.70 
                 0.2676 
                 3.03459 
                 3.96 
               
               
                 34.2598 
                 14.64 
                 0.5353 
                 2.61744 
                 2.35 
               
               
                 36.0523 
                 15.38 
                 0.8029 
                 2.49131 
                 2.47 
               
               
                 38.5046 
                 12.15 
                 0.3346 
                 2.33810 
                 1.95 
               
               
                   
               
               
                 FT-IR analysis returns the spectrum shown in FIG. 2. Said FT-IR spectrum is characterised by the peaks shown in Table 2 below. 
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
           
               
                   
                 TABLE 2 
               
               
                   
                   
               
             
             
               
                   
                 Position: 663.9 
                 Intensity: 68.908 
               
               
                   
                 Position: 698.0 
                 Intensity: 91.597 
               
               
                   
                 Position: 726.1 
                 Intensity: 81.065 
               
               
                   
                 Position: 762.6 
                 Intensity: 81.773 
               
               
                   
                 Position: 775.0 
                 Intensity: 82.082 
               
               
                   
                 Position: 797.3 
                 Intensity: 69.092 
               
               
                   
                 Position: 853.9 
                 Intensity: 85.605 
               
               
                   
                 Position: 000.2 
                 Intensity: 00.946 
               
               
                   
                 Position: 898.4 
                 Intensity: 86.998 
               
               
                   
                 Position: 916.7 
                 Intensity: 87.173 
               
               
                   
                 Position: 978.3 
                 Intensity: 80.897 
               
               
                   
                 Position: 992.9 
                 Intensity: 84.683 
               
               
                   
                 Position: 1026.2 
                 Intensity: 75.777 
               
               
                   
                 Position: 1056.1 
                 Intensity: 80.286 
               
               
                   
                 Position: 1070.1 
                 Intensity: 81.673 
               
               
                   
                 Position: 1122.0 
                 Intensity: 70.931 
               
               
                   
                 Position: 1136.7 
                 Intensity: 74.835 
               
               
                   
                 Position: 1162.7 
                 Intensity: 78.027 
               
               
                   
                 Position: 1196.9 
                 Intensity: 81.770 
               
               
                   
                 Position: 1194.4 
                 Intensity: 81.956 
               
               
                   
                 Position: 1240.1 
                 Intensity: 75.203 
               
               
                   
                 Position: 1255.9 
                 Intensity: 71.745 
               
               
                   
                 Position: 1307.1 
                 Intensity: 83.550 
               
               
                   
                 Position: 1325.0 
                 Intensity: 83.911 
               
               
                   
                 Position: 1365.1 
                 Intensity: 65.044 
               
               
                   
                 Position: 1406.1 
                 Intensity: 84.236 
               
               
                   
                 Position: 1426.2 
                 Intensity: 83.699 
               
               
                   
                 Position: 1115.5 
                 Intensity: 91.206 
               
               
                   
                 Position: 1406.2 
                 Intensity: 79.404 
               
               
                   
                 Position: 1514.8 
                 Intensity: 69.827 
               
               
                   
                 Position: 1557.4 
                 Intensity: 69.604 
               
               
                   
                 Position: 1562.2 
                 Intensity: 71.282 
               
               
                   
                 Position: 1506.7 
                 Intensity: 84.843 
               
               
                   
                 Position: 1660.3 
                 Intensity: 78.785 
               
               
                   
                 Position: 2051.1 
                 Intensity: 94.308 
               
               
                   
                 Position: 2351.3 
                 Intensity: 93.825 
               
               
                   
                 Position: 2872.2 
                 Intensity: 88.379 
               
               
                   
                 Position: 2926.7 
                 Intensity: 88.276 
               
               
                   
                 Position: 2959.4 
                 Intensity: 86.073 
               
               
                   
                 Position: 3076.1 
                 Intensity: 91.143 
               
               
                   
                 Position: 3195.0 
                 Intensity: 89.724 
               
               
                   
                 Position: 3512.4 
                 Intensity: 94.192 
               
               
                   
                   
               
             
          
         
       
     
         [0034]    DSC analysis, shown in  FIG. 3 , highlights an endothermic peak, corresponding to the melting point at about 105.4° C., between 96.6 and 110° C. 
         [0035]    The thermogram shown in  FIG. 4  highlights a continuous loss of weight on moving from about 150 to about 450° C. The characteristic events of the weight loss measured can be observed more clearly on the DTG curve, shown in the same plot. The DTG curve represents the derivative of the thermogram and makes it possible to observe events after 150° C., associated with downgrading of the sample following heating. 
         [0036]    Said crystal form claimed here is obtained from Aliskiren hemifumarate p-xylene solvate. Said solvate form is characterised as follows. 
         [0037]    XRPD analysis of Aliskiren hemifumarate p-xylene solvate makes it possible to obtain the characteristic spectrum shown in  FIG. 5 . The main peaks at 2theta+/−0.3 degrees are: 5.5, 9.2, 10.5, 18.6, 19.7, 21.2. Table 3 below shows the significant peaks of the spectrum. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Pos. 
                 Height 
                 FWHM 
                 d-spacing 
                 Rel. Int. 
               
               
                 [° 2Th.] 
                 [cts] 
                 [° 2Th.] 
                 [Å] 
                 [%] 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 5.5076 
                 4808.51 
                 0.1840 
                 16.04621 
                 100.00 
               
               
                 7.4486 
                 50.00 
                 0.4015 
                 11.86870 
                 1.04 
               
               
                 9.2575 
                 1835.92 
                 0.1506 
                 9.55327 
                 38.18 
               
               
                 9.6953 
                 337.50 
                 0.1171 
                 9.12279 
                 7.02 
               
               
                 10.5420 
                 2724.92 
                 0.2342 
                 8.39194 
                 56.67 
               
               
                 11.8937 
                 168.37 
                 0.4015 
                 7.44108 
                 3.50 
               
               
                 14.0381 
                 202.15 
                 0.2007 
                 6.30883 
                 4.20 
               
               
                 15.7150 
                 329.28 
                 0.1673 
                 5.63921 
                 6.85 
               
               
                 16.1522 
                 407.63 
                 0.1171 
                 5.48755 
                 8.48 
               
               
                 16.7616 
                 155.18 
                 0.2007 
                 5.28939 
                 3.23 
               
               
                 17.3542 
                 46.30 
                 0.2007 
                 5.11008 
                 0.96 
               
               
                 18.6016 
                 1481.76 
                 0.1673 
                 4.77013 
                 30.82 
               
               
                 19.3592 
                 775.22 
                 0.1338 
                 4.58512 
                 16.12 
               
               
                 19.6748 
                 1024.19 
                 0.1004 
                 4.51230 
                 21.30 
               
               
                 20.1082 
                 687.85 
                 0.1338 
                 4.41601 
                 14.30 
               
               
                 20.3377 
                 659.96 
                 0.2007 
                 4.36668 
                 13.72 
               
               
                 21.1619 
                 1389.92 
                 0.1506 
                 4.19843 
                 28.91 
               
               
                 22.3435 
                 183.72 
                 0.1673 
                 3.97901 
                 3.82 
               
               
                 23.2894 
                 594.83 
                 0.1004 
                 3.81950 
                 12.37 
               
               
                 24.4183 
                 986.58 
                 0.2007 
                 3.64543 
                 20.52 
               
               
                 25.6492 
                 271.69 
                 0.2342 
                 3.47320 
                 5.65 
               
               
                 26.5765 
                 241.45 
                 0.3011 
                 3.35409 
                 5.02 
               
               
                 27.9078 
                 65.55 
                 0.5353 
                 3.19703 
                 1.36 
               
               
                 29.2302 
                 72.60 
                 0.2007 
                 3.05534 
                 1.51 
               
               
                 29.7079 
                 89.32 
                 0.2007 
                 3.00729 
                 1.86 
               
               
                 32.0083 
                 146.57 
                 0.2676 
                 2.79622 
                 3.05 
               
               
                 38.1913 
                 30.53 
                 0.5353 
                 2.35655 
                 0.63 
               
               
                   
               
             
          
         
       
     
         [0038]    FT-IR analysis gives the spectrum shown in  FIG. 6 . Said FT-IR spectrum is characterised by the peaks show in Table 4 below. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                 TABLE 4 
               
               
                   
                   
               
             
             
               
                   
                 Position: 663.2 
                 Intensity: 69.543 
               
               
                   
                 Position: 698.6 
                 Intensity: 81.745 
               
               
                   
                 Position: 728.4 
                 Intensity: 81.812 
               
               
                   
                 Position: 776.7 
                 Intensity: 83.333 
               
               
                   
                 Position: 798.1 
                 Intensity: 75.987 
               
               
                   
                 Position: 854.3 
                 Intensity: 87.307 
               
               
                   
                 Position: 898.7 
                 Intensity: 88.710 
               
               
                   
                 Position: 925.0 
                 Intensity: 87.487 
               
               
                   
                 Position: 982.0 
                 Intensity: 82.269 
               
               
                   
                 Position: 996.1 
                 Intensity: 85.292 
               
               
                   
                 Position: 1026.7 
                 Intensity: 79.391 
               
               
                   
                 Position: 1053.1 
                 Intensity: 81.820 
               
               
                   
                 Position: 1073.6 
                 Intensity: 82.624 
               
               
                   
                 Position: 1123.0 
                 Intensity: 78.097 
               
               
                   
                 Position: 1138.6 
                 Intensity: 77.012 
               
               
                   
                 Position: 1162.0 
                 Intensity: 79.417 
               
               
                   
                 Position: 1109.4 
                 Intensity: 01.046 
               
               
                   
                 Position: 1236.9 
                 Intensity: 73.921 
               
               
                   
                 Position: 1256.0 
                 Intensity: 73.153 
               
               
                   
                 Position: 1906.9 
                 Intensity: 89.685 
               
               
                   
                 Position: 1365.6 
                 Intensity: 66.447 
               
               
                   
                 Position: 1425.7 
                 Intensity: 84.092 
               
               
                   
                 Position: 1445.2 
                 Intensity: 81.642 
               
               
                   
                 Position: 1463.7 
                 Intensity: 80.042 
               
               
                   
                 Position: 1514.4 
                 Intensity: 71.805 
               
               
                   
                 Position: 1156.1 
                 Intensity: 79.822 
               
               
                   
                 Position: 1607.3 
                 Intensity: 83.473 
               
               
                   
                 Position: 1662.3 
                 Intensity: 76.725 
               
               
                   
                 Position: 2045.3 
                 Intensity: 94.916 
               
               
                   
                 Position: 2873.1 
                 Intensity: 88.712 
               
               
                   
                 Position: 2930.2 
                 Intensity: 87.270 
               
               
                   
                 Position: 2956.7 
                 Intensity: 86.264 
               
               
                   
                 Position: 3070.4 
                 Intensity: 91.736 
               
               
                   
                 Position: 3192.2 
                 Intensity: 90.300 
               
               
                   
                 Position: 3262.8 
                 Intensity: 90.609 
               
               
                   
                 Position: 3514.0 
                 Intensity: 95.576 
               
               
                   
                   
               
             
          
         
       
     
         [0039]    DSC analysis, shown in  FIG. 7 , shows an endothermic peak, corresponding to the melting point at about 111.0° C., between 101.5 and 118° C. 
         [0040]    The thermogram shown in  FIG. 8  highlights a continuous loss of weight, on moving from about 140 to about 450° C. The characteristic events of the weight loss measured can be observed more clearly on the DTG curve, shown in the same plot. The DTG curve makes it possible to observe a significant event with loss of weight of about 6.15% between 50° C. and 140° C. which corresponds to the loss of solvent following melting of the sample. The other events observed after 150° C. are associated with downgrading of the sample following heating. 
         [0041]    Another object of this invention is Aliskiren hemifumarate, amorphous solid. 
         [0042]    XRPD analysis of said Aliskiren hemifumarate, amorphous solid makes it possible to obtain the characteristic spectrum shown in  FIG. 9 . The main peaks at 2theta+/−0.3 degrees are: 7.3, 10.2, 10.4, 19.6. Table 5 below shows the significant peaks of the spectrum. 
         [0000]                                                          TABLE 5                               Rel. Int.       Pos. [° 2Th.]   Height [cts]   FWHM [° 2Th.]   d-spacing [Å]   [%]                                7.3453   1976.67   0.4349   12.03533   100.00       8.7655   577.68   0.2342   10.08828   29.23       10.1773   1530.19   0.1338   8.69183   77.41       10.3839   1796.14   0.2007   8.51933   90.87       15.0934   138.76   0.5353   5.87003   7.02       19.6590   816.31   0.5353   4.51588   41.30       35.7778   49.34   0.8029   2.50979   2.50                    
FT-IR analysis returns the spectrum shown in  FIG. 10 . Said FT-IR spectrum is characterised by the peaks shown in Table 6 below.
 
         [0000]    
       
         
               
               
               
             
           
               
                   
                 TABLE 6 
               
               
                   
                   
               
             
             
               
                   
                 Position: 665.0 
                 Intensity: 76.922 
               
               
                   
                 Position: 725.2 
                 Intensity: 86.850 
               
               
                   
                 Position: 766.8 
                 Intensity: 87.945 
               
               
                   
                 Position: 798.7 
                 Intensity: 84.949 
               
               
                   
                 Position: 836.2 
                 Intensity: 91.106 
               
               
                   
                 Position: 851.6 
                 Intensity: 90.731 
               
               
                   
                 Position: 898.7 
                 Intensity: 91.806 
               
               
                   
                 Position: 921.7 
                 Intensity: 90.972 
               
               
                   
                 Position: 954.5 
                 Intensity: 90.325 
               
               
                   
                 Position: 981.1 
                 Intensity: 87.554 
               
               
                   
                 Position: 1024.6 
                 Intensity: 85.867 
               
               
                   
                 Position: 1054.8 
                 Intensity: 87.804 
               
               
                   
                 Position: 1121.1 
                 Intensity: 84.478 
               
               
                   
                 Position: 1138.2 
                 Intensity: 84.439 
               
               
                   
                 Position: 1161.4 
                 Intensity: 86.005 
               
               
                   
                 Position: 1187.0 
                 Intensity: 87.166 
               
               
                   
                 Position: 1235.5 
                 Intensity: 83.236 
               
               
                   
                 Position: 1257.0 
                 Intensity: 82.138 
               
               
                   
                 Position: 1306.1 
                 Intensity: 88.174 
               
               
                   
                 Position: 1365.3 
                 Intensity: 78.142 
               
               
                   
                 Position: 1424.6 
                 Intensity: 89.294 
               
               
                   
                 Position: 1443.6 
                 Intensity: 87.930 
               
               
                   
                 Position: 1464.8 
                 Intensity: 86.579 
               
               
                   
                 Position: 1514.4 
                 Intensity: 79.276 
               
               
                   
                 Position: 1556.7 
                 Intensity: 81.856 
               
               
                   
                 Position: 1606.6 
                 Intensity: 88.973 
               
               
                   
                 Position: 1660.0 
                 Intensity: 85.601 
               
               
                   
                 Position: 2871.1 
                 Intensity: 92.567 
               
               
                   
                 Position: 2929.6 
                 Intensity: 92.420 
               
               
                   
                 Position: 2954.2 
                 Intensity: 92.135 
               
               
                   
                 Position: 3190.8 
                 Intensity: 92.973 
               
               
                   
                   
               
             
          
         
       
     
         [0043]    DSC analysis, shown in  FIG. 11 , highlights an endothermic peak, corresponding to the melting point at 98.5° C., between 87 and 07° C. 
         [0044]    The thermogram shown in  FIG. 12  shows a continuous loss of weight starting from about 170° C., loss of weight associated with decomposition of the sample after melting. 
         [0045]    Another object of this invention is the process for the preparation of said crystal form of Aliskiren hemifumarate. In particular, said process comprises:
   i) re-suspending Aliskiren hemifumarate in a suitable solvent, continuously stirred at room temperature in an oil bath;   ii) heating to a suitable temperature until a clear solution is obtained;   iii) cooling, continuing to stir the solution obtained in ii), to room temperature;   iv) stirring of the solution obtained in iii) at a suitable temperature and for a suitable time;   v) filtering of the mix obtained in iv) in order to isolate the precipitate;   vi) drying of the precipitate at a suitable temperature.   
 
         [0052]    In a preferred embodiment, said phase ii) is carried out at a temperature of between 60 and 90° C., preferably at about 75° C. and said solvent is selected in the group that comprises benzene, toluene, xylene, preferably p-xylene. In said phase iii) said cooling is carried out slowly, preferably said solution reaches room temperature in about 5 hours, in oil bath. In said phase iv), said stirring is continued for a further 10 hours or more, preferably for about 12 hours, preferably at room temperature. In said phase vi), said drying takes place at a temperature of between 50 and 90° C., preferably at about 70° C., for about 3 hours. 
         [0053]    The product obtained is the crystal form of Aliskiren hemifumarate claimed in this invention. 
         [0054]    A further object of this invention is the process for the preparation of said amorphous solid of Aliskiren hemifumarate. In particular, said process comprises:
   i) dissolving Aliskiren hemifumarate in alcohol and heating to a suitable temperature;   ii) cooling the solution obtained in i) to room temperature and spiking of the same with pure Aliskiren hemifumarate;   iii) stirring the mix obtained in ii) at a suitable temperature and for a suitable time;   iv) further cooling the mix and continuation of stirring;   v) filtering the mix obtained in iv) so as to isolate the precipitate;   vi) washing the precipitate with alcohol and drying under vacuum at a suitable temperature.   
 
         [0061]    In another preferred embodiment, said phase i) is carried out at a temperature of between 35 and 55° C., more preferably at about 40-45° C., and said alcohol is selected in the group that comprises methanol, ethanol, propanol, butanol, isopropanol, isobutanol, preferably isopropanol. In said phase iii), stirring is continued for 10-20 hours, preferably for about 15 hours, at a temperature of between about 20 and about 25° C. In said phase iv), cooling is carried out preferably at a temperature below 10° C., preferably at a T of between about 0 and about 5° C. and said stirring is continued for a further 2 hours or more. In said phase vi), the alcohol is selected in the group that comprises methanol, ethanol, propanol, butanol, isopropanol, isobutanol, preferably cold isopropanol 
         [0062]    Preferably, said washing is repeated twice. Drying under vacuum is carried out at a temperature below 50° C., preferably below about 40° C. 
         [0063]    The product obtained is the amorphous form of Aliskiren hemifumarate claimed in this invention. 
         [0064]    Said crystal form and said amorphous solid of Aliskiren hemifumarate can be applied in pharmaceutical compositions. The pharmaceutical composition that comprises said crystal form and/or said amorphous solid may contain additives such as sweeteners, aromas, coating substances, inert diluents such as lactose and talcum, binders such as starch, hydroxyethylcellulose, hydroxypropylcellulose and similar. Any conventional technique can be used for preparation of pharmaceutical formulations in accordance with this invention. 
       EXAMPLE 1 
     Preparation of Aliskiren Hemifumarate, Crystal Form 
       [0065]    500 g of Aliskiren hemifumarate were re-suspended in 4 ml of p-xylene, stirring at room temperature in oil bath. The suspension was heated to 75° C. to obtain a clear solution. The solution was then placed in an oil bath in order to bring this, over a period of 5 hours, to room temperature while continuing stirring. Stirring continued for about 12 hours. After filtration, the filtrate was dried at 70° C. for about 3 hours and analysed using XRPD. The product obtained is the crystal form of Aliskiren hemifumarate claimed in this invention. 
       EXAMPLE 2 
     Preparation of Aliskiren Hemifumarate, Amorphous Solid 
       [0066]    100 g of Aliskiren hemifumarate were dissolved in 850 ml of isopropyl alcohol, stirring at 40-45° C. After cooling to room temperature, the mix was spiked with pure Aliskiren hemifumarate and stirred at 20-25° C. for 15 hours. The mix was then cooled to 0-5° C., continuing stirring for another 2 hours. After filtration, the filtrate was washed twice with isopropyl alcohol, using 200 ml of cold isopropyl alcohol for each washing. The washed product was dried under vacuum at 40° C. and analysed by means of XRPD. The product obtained is Aliskiren hemifumarate amorphous form claimed in this invention. 
       EXAMPLE 3 
     Dissolution Test 
       [0067]    Dissolution tests were carried out on Aliskiren hemifumarate, amorphous solid, of this invention and Aliskiren hemifumarate, amorphous solid, obtained as described in WO2008/061622. Kinetic Tests were carried out using a Hanson Vision Classic 6 dissolution tester combined with a Varian Cary 50 UV-Vis spectrophotometer. The program used was “Kinetic” (Cary 50 WinUV software V.3) that continuously recorded absorbance at 280 nm of a buffer solution (80 ml) continuously stirred (100 rpm) at 37° C. to which the sample had been added.  FIG. 13  shows the dissolution speed of Aliskiren hemifumarate, amorphous solid of this invention (curve A) and Aliskiren hemifumarate, amorphous solid obtained as described in WO2008/061622 (curve B). 
       EXAMPLE 4 
     Stability Test 
       [0068]    Stability tests were carried out on Aliskiren hemifumarate, amorphous solid of this invention and Aliskiren hemifumarate, amorphous solid obtained as described in WO2008/061622, maintaining the samples at 25° C., 75% RH. After 2 hours in said conditions, both samples changed from solid to viscous liquid form. The same samples were exposed to 25° C., 60% RH. In these conditions, the diffraction pattern assumed by Aliskiren hemifumarate, amorphous solid, obtained as described in WO2008/061622 is shown in  FIG. 14 , in which curve A is obtained in basal conditions, curve B is obtained after exposure of the sample for 5 days to the conditions indicated.  FIG. 15  shows the diffraction pattern obtained exposing the Aliskiren hemifumarate, amorphous solid of this invention to the same conditions (curve A: basal; curve B: 5 days at 25° C., 60% RH). A comparison of curves A and B of  FIG. 15  reveals that the typical nature of the diffractogram of Aliskiren hemifumarate, amorphous solid of this invention is lost exposing this for 5 days to the conditions indicated. 
       EXAMPLE 5 
     Compressibility Test 
       [0069]    A set of tablets was prepared using different compression forces. A compressibility test was carried out on these. Table 7 shows the data obtained compressing Aliskiren hemifumarate, amorphous solid of this invention; Table 8 refers to Aliskiren hemifumarate, amorphous solid obtained as described in WO2008/061622. 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 7 
               
               
                   
               
               
                 Aliskiren 
                   
                   
                   
                   
                   
               
               
                 hemifumarate 
                 Compression 
                   
                   
                   
                 Rupture 
               
               
                 amorphous 
                 strength 
                 Diameter 
                 Thickness 
                 Weight 
                 Strength 
               
               
                 solid # 
                 (kN) 
                 (mm) 
                 (mm) 
                 (mg) 
                 (N) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 11.83 
                 7.02 
                 1.34 
                 54 
                 4.5 
               
               
                 2 
                 5.83 
                 7.01 
                 1.18 
                 48 
                 4 
               
               
                 3 
                 16.45 
                 7.03 
                 1.2 
                 50 
                 2 
               
               
                 4 
                 10.85 
                 7.00 
                 1.13 
                 45 
                 4 
               
               
                 5 
                 19.43 
                 7.00 
                 1.29 
                 52 
                 3.5 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 8 
               
               
                   
               
               
                 Aliskiren 
                   
                   
                   
                   
                   
               
               
                 hemifumarate 
                 Compression 
                   
                   
                   
                 Rupture 
               
               
                 amorphous 
                 strength 
                 Diameter 
                 Thickness 
                 Weight 
                 Strength 
               
               
                 solid # 
                 (kN) 
                 (mm) 
                 (mm) 
                 (mg) 
                 (N) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 22.27 
                 7.01 
                 1.16 
                 46 
                 1.5 
               
               
                 2 
                 23.82 
                 7.03 
                 1.19 
                 50 
                 2 
               
               
                 3 
                 24.15 
                 7.03 
                 1.22 
                 50 
                 1.5 
               
               
                 4 
                 6.80 
                 6.99 
                 1.12 
                 44 
                 2 
               
               
                 5 
                 7.95 
                 7.04 
                 1.12 
                 46 
                 2 
               
               
                 6 
                 10.10 
                 7.02 
                 1.18 
                 48 
                 1.5 
               
               
                 7 
                 11.55 
                 7.01 
                 1.22 
                 48 
                 2.2 
               
               
                 8 
                 7.88 
                 7.02 
                 1.16 
                 45 
                 2.5 
               
               
                 9 
                 10.15 
                 7.00 
                 1.12 
                 48 
                 2 
               
               
                 10 
                 13.18 
                 7.01 
                 1.23 
                 54 
                 2 
               
               
                 11 
                 15.60 
                 7.04 
                 1.26 
                 53 
                 2 
               
               
                 12 
                 14.12 
                 7.06 
                 1.25 
                 50 
                 2 
               
               
                   
               
             
          
         
       
     
         [0070]    A comparison of the data obtained demonstrated that Aliskiren hemifumarate, amorphous solid of this invention has a higher rupture strength than that observed in tablets of Aliskiren hemifumarate, amorphous solid obtained as described in WO2008/061622.

Technology Category: c