Abstract:
Oxycodone.HCl polymorph forms are disclosed which are useful as analgesic agents either in combination with or as replacements for oxycodone.

Description:
BACKGROUND OF THE INVENTION  
       [0001]     Oxycodone (4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one) is a well-known narcotic analgesic. The hydrochloride salt is commercially used in numerous products, such as Oxycontin, Tylox, and Percocet.  
       SUMMARY OF THE INVENTION  
       [0002]     The present invention is directed to nine novel forms of oxycodone.HCl. These are identified herein as forms A and I-VIII. The known form of the oxycodone.HCl is referred to hereinafter as oxycodone.  
       DETAILED DESCRIPTION OF THE INVENTION  
       [0003]     All nine forms are derived directly or indirectly from oxycodone and are characterized by physical data, most notable by their X-ray powder diffraction patterns expressed in terms of °2θ and the relative intensities of the X-ray diffraction peaks.  
         [0004]     One aspect of the invention is the novel forms of oxycodone. Another aspect is processes to make these novel forms. Since these forms are essentially equally effective as oxycodone itself, they can be used instead of or in combination with oxycodone for its pharmacological effects. The novel forms may be produced and used as the pure form, or the forms may be produced and used in combination with other forms and/or oxycodone. Another aspect of the invention is compositions comprising therapeutically effective amounts of one or more of these novel forms, optionally in combination with oxycodone, and pharmaceutically acceptable carriers therefor. Another aspect is a method of providing an analgesic effect to a mammal, preferably a human, in need thereof which comprises administering to said mammal a therapeutic amount of one or more of a novel form of the invention, optionally in combination with oxycodone. Oxycodone, its therapeutic uses and doses ranges, modes of administration, etc. are all well known in the art.  
         [0005]     By pure is meant that each form of the invention is about 90-100%, preferably 95-100%, more preferably 98-100% (wt./wt.) pure; e.g. free of other oxycodone forms, solvents, and/or other undesirable non-oxycodone impurities. A preferred polymorph of the invention is one which is free of other oxycodone forms, preferably 98-100% free.  
         [0006]     The forms of the invention may be produced by a process which comprises:  
         [0007]     1) dissolving oxycodone in a solvent which comprises water, an organic solvent such as dioxane or ethanol, or a combination of water and a lower alkanol which is ethanol, isopropanol, or butanol, optionally heating said solution as to 60° C., optionally stirring said solution, and optionally evaporating said solvent to precipitate the novel oxycodone form; or  
         [0000]     2) heating Form A to 60-120° C.; or  
         [0000]     3) heating oxycodone to 200° C.  
         [0008]     Another embodiment of the invention is a form of oxycodone made by the process supra, more specifically a form made by a process such as recited in the examples. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0009]      FIG. 1 . is an X-ray powder diffraction pattern of oxycodone expressed in terms of °2θ.  
         [0010]      FIG. 2 . is an X-ray powder diffraction pattern of oxycodone form A expressed in terms of °2θ.  
         [0011]      FIG. 3 . is an X-ray powder diffraction pattern of oxycodone form I expressed in terms of °2θ.  
         [0012]      FIG. 4 . is an X-ray powder diffraction pattern of oxycodone form II expressed in terms of °2θ.  
         [0013]      FIG. 5 . is an X-ray powder diffraction pattern of oxycodone form III expressed in terms of °2θ.  
         [0014]      FIG. 6 . is an X-ray powder diffraction pattern of oxycodone form IV expressed in terms of °2θ.  
         [0015]      FIG. 7 . is an X-ray powder diffraction pattern of oxycodone form V expressed in terms of °2θ.  
         [0016]      FIG. 8 . is an X-ray powder diffraction pattern of oxycodone form VI expressed in terms of °2θ.  
         [0017]      FIG. 9 . is an X-ray powder diffraction pattern of oxycodone form VII expressed in terms of °2θ.  
         [0018]      FIG. 10 . is an X-ray powder diffraction pattern of oxycodone form VIII expressed in terms of °2θ. 
     
    
       [0019]     Table I summarizes the prominent peaks of the X-ray powder diffraction patterns of each oxycodone form. The relative intensity (R.I.) of each peak is shown, wherein R.I. is the ratio of the height of each peak compared to the highest peak, which is designated as 100%.  
         [0020]     The data were generated using either: 
        1) a Shamadzu XRD-6000 X-ray powder diffractometer using Cu Kα radiation, fitted with a fine-focus X-ray tube, set at 40 kV and 40 mA. The divergence and scattering slits were set at 1° and the receiving slit was set at 0.15 mm. Diffracted radiation was detected by a NaI scintillation detector. A theta-two theta continuous scan was used at 3°/min (0.4 sec/0.02° step) from 2.5 to 40 °2θ; or        
 
         [0022]     2) an Inel XRG-300 X-ray powder diffractometer using Cu Kα radiation, fitted with a curved position-sensitive detector, set at 40 kV and 30 mA. Data were collected in real time over a 2-theta range of 120° at a resolution of 0.03°. Samples were packed in a capillary x-ray tube and analyzed with the tube spinning.  
                                                                                                                                                                                       TABLE I                           OXYCODONE ° 2θ PEAKS AND RELATIVE INTENSITIES            Oxy   R.I.   A   R.I.   I   R.I.   II   R.I.   III   R.I.                    8.35   43   7.52   14   7.26   100   6.96   23   7.44   62       10.75   40   7.87   76   10.68   14   7.51   80   7.52   58       12.10   100   10.36   12   11.81   74   10.75   77   7.74   16       14.00   30   10.67   15   13.85   19   11.77   53   7.88   11       14.14   20   11.10   19   16.21   29   12.36   68   11.77   17       16.02   25   11.64   19   17.77   19   13.96   23   16.25   100       16.24   56   11.88   67   20.09   13   15.11   15   18.04   10       17.21   12   13.04   24   24.90   12   16.27   100   20.18   10       17.72   35   15.88   20   26.27   28   17.94   57   25.28   10       18.26   38   16.14   100   27.39   11   20.13   37   25.48   10       19.14   41   17.66   16   32.41   11   20.48   28       19.46   14   17.98   47           20.83   33       20.16   14   19.76   13           21.49   11       20.29   43   20.09   50           22.24   12       20.72   13   20.66   28           23.76   11       21.60   12   20.88   15           25.30   57       21.81   14   21.41   17           25.58   34       23.54   15   22.72   12           25.76   17       24.04   21   22.98   13           26.26   15       25.22   24   23.99   11           27.60   13       26.09   12   25.06   33           28.07   12       26.87   10   25.57   48           30.41   15       28.17   19   26.17   12           31.37   11       28.36   11   28.96   30           35.93   11       29.01   14   30.25   16       30.02   17   31.10   14       30.18   12   38.31   13                    IV   R.I.   V   R.I.   VI   R.I.   VII   R.I.   VIII   R.I.                    7.38   37   6.85   19   7.31   100   7.94   31   10.50   13       10.59   51   7.16   28   10.70   41   8.16   55   10.81   100       11.84   78   7.37   100   11.80   51   8.40   10   12.28   17       13.97   22   11.48   30   12.48   10   10.52   10   12.58   64       14.91   12   19.47   18   13.90   25   10.73   21   12.72   76       16.01   65   22.20   11   14.89   16   11.24   30   12.92   73       16.24   14   22.35   15   16.30   56   11.78   44   13.08   57       17.44   36           17.87   49   12.02   24   13.24   38       17.62   100           18.86   10   12.40   48   13.42   19       18.19   24           19.85   10   13.83   22   14.50   15       19.02   10           20.17   30   14.00   12   14.64   14       19.51   13           20.54   16   15.82   11   24.04   16       19.95   75           21.48   14   16.18   100   24.14   22       20.67   14           21.99   16   17.64   15   24.52   35       21.08   26           22.47   11   18.00   14   24.64   43       21.31   22           24.47   22   18.16   21   24.76   24       21.87   12           25.35   11   18.88   14   27.31   28       22.55   17           25.55   19   19.10   14   28.17   10       24.34   45           26.40   24   19.36   11       25.11   56           26.65   24   19.50   11       25.36   26           27.56   25   20.14   21       26.58   45           30.68   19   20.48   22       27.32   10           32.56   16   21.06   20       27.59   27           35.12   10   21.91   11       28.01   15           37.84   11   23.86   12       29.36   10                   24.08   32       30.14   13                   25.04   22       30.38   34                   25.38   50       31.20   12                   25.58   29       34.26   12                   27.89   12       34.58   11                   29.23   11       35.35   14                   30.33   21       36.36   18                  
 
         [0023]     Table II summarizes the peaks of the X-ray powder diffraction patterns of each oxycodone form that are either unique (peaks that are not shared with other forms within ±0.20 °2θ) or intense (R.I.≧15).  
                                                                                           TABLE II                           SIGNIFICANT OXYCODONE ° 2θ PEAKS            A   I   II   III   IV   V   VI   VII   VIII                    7.87   7.26   7.51   7.44   11.84   6.85   7.31   8.16   10.81       11.88   11.81   10.75   7.52   16.01   7.16   11.80   12.40   12.58       16.14   16.21   12.36   11.77   17.62   7.37   16.30   16.18   12.72       20.09   26.27   16.27   16.25   19.95   11.48   17.87   25.38   12.92       22.98   32.41   35.93       34.26       30.68       38.31               34.58       32.56                       35.35       37.84                       36.36                  
 
         [0024]     The invention is further defined by reference to the following examples, which are intended to be illustrative and not limiting.  
       EXAMPLE 1  
     Preparation of Form A  
       [0025]     Oxycodone, 29.8 mg, and 75:25 ethanol/water, 0.8 mL, were combined in a vial, which was sonicated to dissolve the solids. The sample was filtered (0.2 μm nylon filter) and allowed to evaporate uncapped to dryness to yield Form A.  
       EXAMPLE 2  
     Preparation of Form I  
       [0026]     Oxycodone, 50.0 mg, and water, 0.3 mL, were combined in a vial, which was sonicated to dissolve the solids. The sample was filtered (0.2 μm nylon filter) and allowed to evaporate uncapped to dryness to yield Form I.  
       EXAMPLE 3  
     Preparation of Form II  
       [0027]     Oxycodone, 199.4 mg, and 95:5 ethanol/water, 2 mL, were combined in a vial to form a cloudy sample, which was agitated at 60° C. The sample was filtered (0.2 μm nylon filter) and allowed to evaporate very slowly, i.e. covered with foil containing 1 pinhole, to yield Form II.  
       EXAMPLE 4  
     Preparation of Form III  
       [0028]     Oxycodone, 100.5 mg, and ethanol, 1.6 mL, were combined in a vial, which was stirred for approximately 10 min. at 60° C. The sample was filtered (0.2 μm nylon filter) into a clean vial and cooled to 20° C. covered to yield Form III.  
       EXAMPLE 5  
     Preparation of Form IV  
       [0029]     Oxycodone, 49.8 mg, and dioxane, 18 mL, were combined in a vial to form a cloudy sample, which was stirred at ambient temperature overnight. The resultant solids were collected by vacuum filtration to yield Form IV.  
       EXAMPLE 6  
     Preparation of Form V  
       [0030]     Oxycodone, 50.0 mg, and 92:8 butanol/water, 3.3 mL, were combined in a vial, which was sonicated to dissolve solids. The sample was filtered (0.2 μm nylon filter) and allowed to evaporate uncapped to dryness to yield Form V.  
       EXAMPLE 7  
     Preparation of Form VI  
       [0031]     Oxycodone, 50.8 mg, and 92:8 isopropanol/water, 6 mL, were combined in a vial, which was sonicated to dissolve solids. The sample was filtered (0.2 μm nylon filter) and allowed to evaporate very slowly, i.e. covered with foil containing 1 pinhole, to dryness to yield Form VI.  
       EXAMPLE 8  
     Preparation of Form VII  
       [0032]     Oxycodone Form A was heated to 60-120° C. on a variable temperature XRPD for less than 30 min. to yield Form VII.  
       EXAMPLE 9  
     Preparation of Form VIII  
       [0033]     Oxycodone was heated to 200° C. on a variable temperature XRPD for less than 30 min. to yield Form VIII.