Abstract:
Hydrocodone bitartrate forms are disclosed which are useful as analgesic agents either in combination with or as replacements for hydrocodone bitartrate.

Description:
BACKGROUND OF THE INVENTION  
       [0001]     Hydrocodone (4,5a-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5), dihydrocodeinone) is a semi synthetic opioid structurally related to codeine and is approximately equipotent to morphine in producing opiate-like effects. It is also known as hydrocodone bitartrate. Hydrocodone bitartrate is well known as an antitussive agent and an effective analgesic for mild to moderate pain control. In its most usual product forms hydrocodone bitartrate is combined with acetaminophen, aspirin, ibuprofen, and antihistamines. It is commercially available in tablet, capsule, and liquid forms. Hydrocodone bitartrate is available as Vicodin®, Lortab®, Vicoprofen®, Tussionex®, Hycomine®, and many other products. The drug is most often administered orally, typically in dosage forms of 5, 7.5, and 10 mg.  
       SUMMARY OF THE INVENTION  
       [0002]     The present invention is directed to ten novel forms of hydrocodone bitartrate. These are identified herein as Forms II-X and an amorphous form. The known form of hydrocodone bitartrate is referred to hereinafter as hydrocodone bitartrate Form I.  
       DETAILED DESCRIPTION  
       [0003]     All ten forms are derived directly or indirectly from hydrocodone bitartrate (hydrocodone bitartrate Form I) and are characterized by physical data, most notable by their X-ray powder diffraction XRPD 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 hydrocodone bitartrate. Another aspect of this invention is processes to make these novel forms. These novel forms of hydrocodone bitartrate can be used instead of or in combination with hydrocodone bitartrate 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 the other novel forms and/or hydrocodone bitartrate Form I. Another aspect of the invention is compositions comprising therapeutically effective amounts of one or more of these novel forms, optionally in combination with hydrocodone bitartrate Form I, and pharmaceutically acceptable carriers therefor. Another aspect is a method of providing a therapeutic (e.g., 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 hydrocodone bitartrate. Hydrocodone bitartrate, its therapeutic uses and dose 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 hydrocodone bitartrate forms, solvents, and/or other undesirable non-hydrocodone bitartrate impurities. A preferred form of the invention is one that is free of other hydrocodone bitartrate forms, preferably 98-100% free.  
         [0006]     One embodiment of the invention is the forms of hydrocodone bitartrate made by the processes such as recited in the examples. Another embodiment of the invention is the forms of hydrocodone bitartrate as identified by the X-ray powder diffraction patterns shown below. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0007]     FIG. 1 is an X-ray powder diffraction pattern of hydrocodone bitartrate Form I expressed in terms of °2θ.  
         [0008]     FIG. 2 is an X-ray powder diffraction pattern of hydrocodone bitartrate Form II expressed in terms of °2θ.  
         [0009]     FIG. 3 is an X-ray powder diffraction pattern of hydrocodone bitartrate Form III expressed in terms of °2θ.  
         [0010]     FIG. 4 is an X-ray powder diffraction pattern of hydrocodone bitartrate Form IV expressed in terms of °2θ.  
         [0011]     FIG. 5 is an X-ray powder diffraction pattern of hydrocodone bitartrate Form V expressed in terms of °2θ.  
         [0012]     FIG. 6 is an X-ray powder diffraction pattern of hydrocodone bitartrate Form VI expressed in terms of °2θ.  
         [0013]     FIG. 7 is an X-ray powder diffraction pattern of hydrocodone bitartrate Form VII expressed in terms of °2θ.  
         [0014]     FIG. 8 is an X-ray powder diffraction pattern of hydrocodone bitartrate Form VIII expressed in terms of °2θ.  
         [0015]     FIG. 9 is an X-ray powder diffraction pattern of hydrocodone bitartrate Form IX expressed in terms of °2θ.  
         [0016]     FIG. 10 is an X-ray powder diffraction pattern of hydrocodone bitartrate Form X expressed in terms of °2θ.  
         [0017]     FIG. 11 is an X-ray powder diffraction pattern of hydrocodone bitartrate, amorphous form expressed in terms of °2θ.  
     
    
       [0018]     Tables I and II summarize the prominent peaks of the X-ray powder diffraction patterns of each hydrocodone bitartrate form. The relative intensity (R.I.) (I/Io≧10) 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%.  
         [0019]     The data were generated using a Shimadzu v 4.1 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 10 and the receiving slit was set at 0.15 mm. Diffracted radiation was detected by a Nal 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.  
       Tables I &amp; II  
     Hydrocodone XRPD °2θ Peaks and Relative Intensities  
       [0020]    
       
         
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE I 
               
             
             
               
                   
               
               
                   
               
               
                 Form I 
                 Form II 
                 Form III 
                 Form IV 
                 Form V 
               
             
          
           
               
                 °2θ 
                 I/Io 
                 °2θ 
                 I/Io 
                 °2θ 
                 I/Io 
                 °2θ 
                 I/Io 
                 °2θ 
                 I/Io 
               
               
                   
               
             
          
           
               
                 5.25 
                 11 
                 10.39 
                 100 
                 4.86 
                 14 
                 7.54 
                 22 
                 6.57 
                 56 
               
               
                 6.90 
                 10 
                 10.66 
                 11 
                 6.74 
                 10 
                 11.21 
                 66 
                 8.96 
                 27 
               
               
                 9.01 
                 15 
                 14.36 
                 12 
                 8.82 
                 21 
                 12.09 
                 16 
                 12.16 
                 30 
               
               
                 9.48 
                 21 
                 16.61 
                 12 
                 9.10 
                 13 
                 15.24 
                 57 
                 14.54 
                 53 
               
               
                 10.22 
                 13 
                 16.98 
                 14 
                 9.40 
                 19 
                 15.66 
                 24 
                 15.16 
                 10 
               
               
                 10.48 
                 100 
                 17.13 
                 43 
                 10.40 
                 100 
                 17.87 
                 16 
                 19.88 
                 14 
               
               
                 11.98 
                 45 
                 18.32 
                 28 
                 13.44 
                 22 
                 19.21 
                 49 
                 20.76 
                 100 
               
               
                 13.89 
                 67 
                 20.86 
                 27 
                 14.16 
                 23 
                 19.98 
                 19 
                 22.62 
                 12 
               
               
                 14.26 
                 14 
                 21.22 
                 17 
                 14.61 
                 12 
                 21.74 
                 11 
                 24.04 
                 17 
               
               
                 15.80 
                 17 
                 21.37 
                 53 
                 16.30 
                 45 
                 22.80 
                 100 
                 24.82 
                 15 
               
               
                 17.22 
                 35 
                 23.01 
                 25 
                 16.64 
                 24 
                 23.54 
                 18 
               
               
                 17.38 
                 24 
                 24.81 
                 19 
                 16.96 
                 35 
                 24.58 
                 26 
               
               
                 18.68 
                 20 
                 27.17 
                 12 
                 17.48 
                 19 
                 25.02 
                 27 
               
               
                 18.99 
                 21 
                 28.29 
                 10 
                 18.91 
                 10 
               
               
                 20.52 
                 11 
                 30.24 
                 19 
                 19.94 
                 60 
               
               
                 20.78 
                 54 
                 33.55 
                 20 
                 20.33 
                 40 
               
               
                 22.80 
                 62 
                   
                   
                 21.78 
                 20 
               
               
                 23.06 
                 36 
                   
                   
                 22.24 
                 10 
               
               
                 24.12 
                 22 
                   
                   
                 22.60 
                 16 
               
               
                 24.26 
                 13 
                   
                   
                 23.57 
                 51 
               
               
                 26.06 
                 19 
                   
                   
                 23.96 
                 12 
               
               
                 26.32 
                 21 
                   
                   
                 24.41 
                 14 
               
               
                 27.30 
                 39 
                   
                   
                 25.38 
                 18 
               
               
                 27.58 
                 29 
                   
                   
                 26.74 
                 35 
               
               
                 28.02 
                 12 
                   
                   
                 27.42 
                 34 
               
               
                 29.31 
                 16 
                   
                   
                 27.68 
                 17 
               
               
                 34.26 
                 15 
                   
                   
                 29.51 
                 10 
               
               
                 39.26 
                 17 
                   
                   
                 30.87 
                 19 
               
               
                   
                   
                   
                   
                 31.54 
                 10 
               
               
                   
                   
                   
                   
                 36.40 
                 11 
               
               
                   
               
             
          
         
       
     
         [0021]    
       
         
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE II 
               
             
             
               
                   
               
               
                   
               
               
                 Form VI 
                 Form VII 
                 Form VIII 
                 Form IX 
                 Form X 
               
             
          
           
               
                 °2θ 
                 I/Io 
                 °2θ 
                 I/Io 
                 °2θ 
                 I/Io 
                 °2θ 
                 I/Io 
                 °2θ 
                 I/Io 
               
               
                   
               
             
          
           
               
                 6.54 
                 12 
                 6.90 
                 40 
                 6.82 
                 16 
                 5.28 
                 47 
                 8.75 
                 36 
               
               
                 6.85 
                 51 
                 9.42 
                 12 
                 7.35 
                 100 
                 8.21 
                 10 
                 9.67 
                 18 
               
               
                 9.39 
                 40 
                 9.56 
                 14 
                 9.79 
                 56 
                 12.66 
                 52 
                 10.56 
                 100 
               
               
                 12.54 
                 36 
                 13.08 
                 42 
                 12.70 
                 49 
                 13.81 
                 19 
                 11.28 
                 24 
               
               
                 12.92 
                 62 
                 15.22 
                 20 
                 13.00 
                 64 
                 15.02 
                 20 
                 13.51 
                 26 
               
               
                 13.30 
                 37 
                 20.37 
                 25 
                 14.70 
                 57 
                 16.32 
                 58 
                 14.82 
                 34 
               
               
                 14.10 
                 28 
                 20.85 
                 24 
                 16.04 
                 39 
                 17.78 
                 73 
                 15.80 
                 19 
               
               
                 15.23 
                 48 
                 21.38 
                 71 
                 16.78 
                 11 
                 18.70 
                 42 
                 16.04 
                 35 
               
               
                 16.62 
                 78 
                 21.64 
                 81 
                 17.08 
                 12 
                 19.74 
                 85 
                 16.32 
                 16 
               
               
                 17.00 
                 24 
                 21.98 
                 100 
                 18.11 
                 37 
                 22.22 
                 100 
                 17.61 
                 20 
               
               
                 18.01 
                 100 
                 27.95 
                 11 
                 19.43 
                 14 
                 23.80 
                 29 
                 18.07 
                 28 
               
               
                 18.82 
                 15 
                 28.70 
                 13 
                 22.27 
                 33 
                 24.86 
                 12 
                 19.26 
                 24 
               
               
                 19.67 
                 23 
                 35.03 
                 11 
                 23.07 
                 49 
                 26.33 
                 37 
                 20.30 
                 42 
               
               
                 20.75 
                 43 
                   
                   
                 24.33 
                 10 
                 28.52 
                 26 
                 20.78 
                 13 
               
               
                 21.22 
                 24 
                   
                   
                 25.50 
                 78 
                 29.86 
                 16 
                 21.33 
                 26 
               
               
                 21.85 
                 92 
                   
                   
                 26.54 
                 34 
                 31.92 
                 12 
                 21.98 
                 14 
               
               
                 23.21 
                 17 
                   
                   
                 28.62 
                 13 
                 33.21 
                 19 
                 22.87 
                 41 
               
               
                 23.76 
                 16 
                   
                   
                 32.09 
                 17 
                 34.67 
                 16 
                 24.00 
                 14 
               
               
                 24.52 
                 27 
                   
                   
                   
                   
                 38.15 
                 25 
                 24.28 
                 19 
               
               
                 26.15 
                 48 
                   
                   
                   
                   
                 39.54 
                 11 
                 26.06 
                 43 
               
               
                 27.74 
                 14 
                   
                   
                   
                   
                   
                   
                 26.44 
                 25 
               
               
                 28.06 
                 30 
                   
                   
                   
                   
                   
                   
                 26.78 
                 17 
               
               
                 28.52 
                 10 
                   
                   
                   
                   
                   
                   
                 27.45 
                 22 
               
               
                 28.91 
                 30 
                   
                   
                   
                   
                   
                   
                 27.80 
                 11 
               
               
                 29.38 
                 13 
                   
                   
                   
                   
                   
                   
                 28.06 
                 14 
               
               
                 30.03 
                 11 
                   
                   
                   
                   
                   
                   
                 28.26 
                 12 
               
               
                 31.40 
                 33 
                   
                   
                   
                   
                   
                   
                 30.86 
                 11 
               
               
                 31.88 
                 12 
                   
                   
                   
                   
                   
                   
                 38.11 
                 11 
               
               
                 32.74 
                 10 
               
               
                 34.46 
                 10 
               
               
                 35.14 
                 29 
               
               
                 35.66 
                 20 
               
               
                 35.96 
                 11 
               
               
                 37.28 
                 13 
               
               
                 37.80 
                 10 
               
               
                 38.58 
                 22 
               
               
                 39.08 
                 11 
               
               
                   
               
             
          
         
       
     
         [0022]     Table III summarizes the peaks of the X-ray powder diffraction patterns of each hydrocodone bitartrate form that are unique (peaks that are not shared with other forms within ±0.20 °2θ) and/or four additional intense peaks to make up a unique set for each form.  
                                                                                                   TABLE III                           Crystalline Hydrocodone Bitartrate XRPD Unique Peaks                                    Form   Form               Form I   Form II   Form III   Form IV   Form V   Form VI   VII   VIII   Form IX   Form X                     9.48   10.39*   4.86   7.54   6.57   12.54   13.08   7.35*   8.21   8.75        10.48*   17.13   6.74   11.21   12.16   12.92   21.64   14.70   12.66   10.56*       11.98   18.32   8.82   19.21   14.54   18.01*   21.98*   25.50   17.78   18.07       26.06   21.37   10.40*   22.80*   20.76*   26.15   28.70   26.54   19.74   22.87       —   23.01   26.74   25.02   —   28.91   —   —   22.22*   —       —   30.24   36.40   —   —   32.74   —   —       —       —   33.55   —   —   —       —   —       —                 *Denotes the peak of greatest intensity for each form             
 
         [0023]     Table IV summarizes the peaks of the X-ray powder diffraction patterns of the amorphous hydrocodone bitartrate form as generated by a Shimadzu v 4.1 X-ray powder diffractometer.  
                             TABLE IV                           Amorphous Hydrocodone Bitartrate XRPD Peak Ranges                    Amorphous               form           Peak No.   Range (°2θ)                       1   7.28-30.76                      
 
         [0024]     The forms of the invention may be further defined by other physical properties such as those in Table V.  
                                 TABLE V                           Unique Properties of Hydrocodone Bitartrate Polymorphs                Form   Unique Properties   Comments                       I   DSC* (endotherms)   74, 118° C.               Hot stage Melt   116° C.               Water/Volatiles   water (2.1 moles)               (content)           II   DSC (endotherms)   101° C.               Hot stage Melt   131° C.               Water/Volatiles   water (1.8 moles)               (content)           III   DSC (endotherms)   91, 99° C.               Hot stage Melt   106° C.               Water/Volatiles   water (3 moles)               (content)           IV   DSC (endotherms)   91, 129° C.               Hot stage Melt   129° C.               Water/Volatiles   water (0.4 mole)               (content)           V   DSC (endotherms)   69, 87° C.               Hot stage Melt   81° C.               Water/Volatiles   water (2 moles)               (content)           VI   DSC (endotherms)   93, 100° C.               Hot stage Melt   104° C.               Water/Volatiles   water (2.3 moles)               (content)           VII   DSC (endotherms)   103, 105° C.               Hot stage Melt   96° C.               Water/Volatiles   water (2.3 moles)               (content)           VIII   DSC (endotherms)   109° C.               Water/Volatiles   acetonitrile (1 mole)               (content)           Amorphous   DSC   Glass Transition (T g )           form       onset at 101° C.                         * Differential scanning calorimetry             
 
         [0025]     One of skill in the art will know how to determine “Hot stage Melt” temperature. Briefly, hot stage melt is determined by placing a sample of the compound on a glass microscope stage and slowly increasing the temperature of the stage until melting of the compound is observed.  
         [0026]     As used herein the term “hydrocodone bitartrate” when used alone and without modifiers, refers to the known form or Form I of hydrocodone bitartrate.  
         [0027]     The invention is further defined by reference to the following examples, which are intended to be illustrative and not limiting.  
       EXAMPLE 1  
       [0000]     Preparation of Form II  
         [0028]     755 mg of hydrocodone bitartrate was dissolved in 13 mL of a 9:1 (v/v) water: ethanol. 2 mL of the solution was filtered through a 0.2-μm nylon syringe filter, placed in a fume hood uncapped for evaporation to dryness to yield the title form.  
       EXAMPLE 2  
       [0000]     Preparation of Form III  
         [0029]     1000 mg of hydrocodone bitartrate was dissolved in 17 mL of water. ˜2 mL of the solution was filtered through a 0.2 μm nylon syringe filter, 16 mL of acetone was added to the filtrate. The solution was placed in a refrigerator at ˜4° C. for 4 days, then placed in a freezer (−20° C.) for 1 day. The solid formed was vacuum filtered to afford the title form.  
       EXAMPLE 3  
       [0000]     Preparation of Form IV  
         [0030]     1000 mg of hydrocodone bitartrate was dissolved in 17 mL of water. 2 mL of the solution was filtered through a 0.2 μm nylon syringe filter, placed in a fume hood uncapped for evaporation to dryness, and dried under vacuum for 4 days to yield the title form.  
       EXAMPLE 4  
       [0000]     Preparation of Form V  
         [0031]     338 mg of hydrocodone bitartrate was dissolved in 7.5 mL of water. The solution was filtered through a 0.2 μm nylon syringe filter, added acetone (72.5 mL) to the filtrate. The solution was covered and placed in a freezer (−20° C.) for 5 days. The title form was then collected through vacuum filtration.  
       EXAMPLE 5  
       [0000]     Preparation of Form VI  
         [0032]     80 mg of hydrocodone bitartrate was dissolved in 20 mL of tetrahydrofuran at 60° C. The solution was filtered while warm and allowed to cool slowly to room temperature. After several hours of cooling, the sample was placed in a refrigerator (4° C.) for 3 days, and a freezer (−20° C.) for 8 days. The solids formed were collected through vacuum filtration, and dried under vacuum to yield the title form.  
       EXAMPLE 6  
       [0000]     Preparation of Form VII  
         [0033]     81 mg of hydrocodone bitartrate was dissolved in 13 mL of methanol and filtered through a 0.2 μm nylon syringe filter, The solution was placed in a freezer (−20° C.) for 9 days the solids formed were removed by vacuum filtration. Seven (7) mL of cooled ethyl ether was added to the filtered solution, covered and placed back into the freezer (−20° C.) for 39 days. The solid formed was vacuum filtered to yield the title form.  
       EXAMPLE 7  
       [0000]     Preparation of Form VIII  
         [0034]     95 mg of hydrocodone bitartrate was dissolved in 20 mL of acetonitrile. 5 mL of the solution was filtered through a 0.2 μm nylon syringe filter, left loosely capped in a fume hood to dryness to yield the title form.  
       EXAMPLE 8  
       [0000]     Preparation of Form IX  
         [0035]     802 mg of hydrocodone bitartrate was dissolved in 200 mL of tetrahydrofuran at 60° C. Half the solution was poured into a pre-warmed beaker, which was then placed in a dry ice/acetone bath. The beaker was then covered and placed in a freezer (−20° C.) for 26 days. The solids formed were removed by vacuum filtration. The filtrate was left uncovered in a fume hood to dryness to yield the title form.  
       EXAMPLE 9  
       [0000]     Preparation of Form X  
         [0036]     104 mg of hydrocodone bitartrate was dissolved in 20 mL of acetonitrile. The solution was filtered through a 0.2 μm nylon syringe filter and covered with a foil lid containing 5 pinholes, and left in a fume hood to dryness to yield the title form.  
       EXAMPLE 10  
       [0000]     Preparation of Amorphous Form  
         [0037]     43 mg of hydrocodone bitartrate was dissolved in 10 mL of tetrahydrofuran and 2 mL water. Half the solution was filtered through a 0.2-micrometer nylon syringe filter and the solution was allowed to evaporate without a cover (completely evaporated after 1 day) to yield the title form.