Patent Publication Number: US-9428516-B1

Title: Crystalline forms of morphine sulfate

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of U.S. patent application Ser. No. 14/670,493, filed Mar. 27, 2015, the disclosures of which are incorporated herein by reference in their entireties for all purposes. 
    
    
     FIELD OF THE INVENTION 
     The present disclosure relates to crystalline forms of morphine sulfate, and methods for making the same. The present disclosure also relates to pharmaceutical compositions containing morphine sulfate and methods for treating pain using such compositions. 
     BACKGROUND OF THE INVENTION 
     Morphine is the most abundant of at least 50 alkaloids found in opium, poppy and poppy derivatives,  Papaver somniferum . Poppy straw is opium poppy ( Poppy somniferum ) that is harvested when fully mature and dry, minus the ripe poppy seeds. An agricultural by-product of the poppy seed harvest, the straw was a waste product before the 1930s when a chemical process became available to extract morphine from it. Poppy straw consisting mainly of the capsule became a valuable source of morphine. Today, poppy straw is a major source of many opioids and other alkaloids. It is the source of 90% of the world supply of legal morphine (i.e. for medical and scientific use). 
     During processing, poppy straw is pulverized and washed many times in water and/or various acids and other chemicals to produce poppy straw concentrate (PSC) or concentrated poppy straw (CPS). Once dried, the concentrate is a beige to brown colored powder and contains salts of various alkaloids. It can range from about 9 to 30 times the morphine concentration of poppy straw. Morphine is generally 8% to 17% of the dry weight of opium, although specially-designed cultivars reach 26% or produce little morphine at all. The latter varieties, including the Przemko and Norman strains of the opium poppy, are used to produce two other alkaloids, thebaine and oripavine, which are used in the manufacture of semi-synthetic opioids like oxycodone and etorphine as well as other types of drugs. At least one manufacturer, Tasmanian Alkaloids, produces both high-morphine and high-thebaine/oripavine types of CPS. 
     Morphine is produced most predominantly early in the life cycle of the plant and, past the optimum point for extraction, various processes in the plant produce codeine, thebaine, and in some cases low quantities of hydromorphone, dihydromorphine, dihydrocodeine, tetrahydrothebaine and hydrocodone. 
     Morphine, generally administered in a salt form, is a potent opiate analgesic, for the relief of moderate to severe pain, and has been approved for use for decades. It can be administered as an injectable solution, suppository, capsule, tablet or extended release product. Like other opioids, e.g. oxycodone, hydromorphone and diacetylmorphine (heroin), morphine acts directly on the central nervous system (CNS) to relieve pain. Today, morphine sulfate is sold under various trade names including Astramorph PF™, Avinza®, DepoDur®, Duramorph, Infumorph, Kadian®, MS-Contin®, Oramorph® SR and RMS. Kadian® is a morphine sustained-release dosage form for once or twice per day dosing. Kadian® is currently available in 10, 20, 30, 40, 50, 60, 80, 100 and 200 mg morphine sulfate extended release capsules. 
     Morphine is regarded as the opioid drug of choice in the treatment of cancer pain, for example. Side effects of morphine treatment include, for example, nausea and vomiting, constipation, sedation, confusion and loss of appetite. It has been suggested that the use of modified release morphine formulations, apart from their convenience and their ability to provide continuous analgesia, may also result in a lower incidence and severity of morphine-related side effects. Sustained-release morphine dosage forms are described in U.S. Pat. Nos. 5,202,128, 5,215,758, 5,378,474 and 5,672,360. 
     All references cited herein, including the morphine sulfate products associated with the above-mentioned trade names, are incorporated herein by reference in their entireties. 
     SUMMARY OF THE INVENTION 
     The present disclosure is directed to eight novel crystalline forms of morphine sulfate. These forms are identified herein as Forms α, β, γ, δ, ε, ζ, η and θ. The present disclosure is further directed to processes for the preparation of the crystalline forms of morphine sulfate as herein described. 
     Illustrative of the present disclosure is a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and any of the crystalline forms of morphine sulfate as herein described. An illustration of the present disclosure is a pharmaceutical composition made by mixing any of the crystalline forms of morphine sulfate as herein described and at least one pharmaceutically acceptable excipient. Illustrating the present disclosure is a process for making a pharmaceutical composition comprising mixing any of the crystalline forms of morphine sulfate as herein described and at least one pharmaceutically acceptable excipient. 
     Exemplifying the present disclosure are methods of treating pain, comprising administering to a subject in need thereof, one or more of the morphine sulfate crystalline forms or pharmaceutical compositions described above. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is an X-ray powder diffractogram of morphine free base, expressed in terms of ° 2θ. 
         FIG. 2  is an X-ray powder diffractogram of morphine sulfate crystalline Form α, expressed in terms of ° 2θ. 
         FIG. 3  is an X-ray powder diffractogram of morphine sulfate crystalline Form β, expressed in terms of ° 2θ. 
         FIG. 4  is an X-ray powder diffractogram of morphine sulfate crystalline Form γ, expressed in terms of ° 2θ. 
         FIG. 5  is an X-ray powder diffractogram of morphine sulfate crystalline Form δ, expressed in terms of ° 2θ. 
         FIG. 6  is an X-ray powder diffractogram of morphine sulfate crystalline Form ε, expressed in terms of ° 2θ. 
         FIG. 7  is an X-ray powder diffractogram of morphine sulfate crystalline Form ζ, expressed in terms of ° 2θ. 
         FIG. 8  is an X-ray powder diffractogram of morphine sulfate crystalline Form η, expressed in terms of ° 2θ. 
         FIG. 9  is an X-ray powder diffractogram of morphine sulfate crystalline Form θ, expressed in terms of ° 2θ. 
         FIG. 10  is a measured differential scanning calorimetry thermogram of morphine free base. 
         FIG. 11  is a measured differential scanning calorimetry thermogram of morphine sulfate crystalline Form α. 
         FIG. 12  is a measured differential scanning calorimetry thermogram of morphine sulfate crystalline Form β. 
         FIG. 13  is a measured differential scanning calorimetry thermogram of morphine sulfate crystalline Form γ. 
         FIG. 14  is a measured differential scanning calorimetry thermogram of morphine sulfate crystalline Form δ. 
         FIG. 15  is a measured differential scanning calorimetry thermogram of morphine sulfate crystalline Form ε. 
         FIG. 16  is a measured differential scanning calorimetry thermogram of morphine sulfate crystalline Form ζ. 
         FIG. 17  is a measured differential scanning calorimetry thermogram of morphine sulfate crystalline Form η. 
         FIG. 18  is a measured differential scanning calorimetry thermogram of morphine sulfate crystalline Form θ. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present disclosure is directed to eight novel crystalline forms of morphine sulfate, as herein described in detail. More particularly, the present disclosure is directed to novel crystalline Forms α, β, γ, δ, ε, ζ, η and θ of morphine sulfate. 
     The present disclosure is further directed to processes for the preparation of the crystalline forms of morphine sulfate, as described in more detail in the Examples which follow herein. 
     The present disclosure is further directed to pharmaceutical compositions comprising one or more of the crystalline forms of morphine sulfate. The present disclosure is further directed to a method of treating pain comprising administering to a subject in need thereof, one or more of the forms of morphine sulfate. 
     The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. 
     The term “excipient” as used herein refers to a pharmaceutically acceptable organic or inorganic carrier substance. Excipients may be natural or synthetic substances formulated alongside the active ingredient of a medication, included for the purpose of bulking-up formulations that contain potent active ingredients (thus often referred to as “bulking agents,” “fillers,” or “diluents”), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption or solubility. Excipients can also be useful in the manufacturing process, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation over the expected shelf life. 
     The term “subject” as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. Further, a subject may not have exhibited any symptoms of the disorder, disease or condition to be treated and/prevented, but has been deemed by a physician, clinician or other medical professional to be at risk for developing said disorder, disease or condition. 
     The terms “treating,” “treatment” and the like as used herein shall include the management and care of a subject (preferably a mammal, more preferably a human) for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure to prevent the onset of the symptoms or complications, alleviate the symptoms or complications, or eliminate the disease, condition, or disorder. 
     The crystalline forms of morphine sulfate of the present disclosure may be prepared directly or indirectly from morphine free base. Examples 1-10, which follow herein, provide embodiments of the preparation of the crystalline forms of morphine sulfate. 
     The crystalline forms of morphine sulfate herein described may be characterized by one or more of their characteristic physical properties including, but not limited to, X-ray powder diffraction peaks and differential scanning calorimetry. 
     The crystalline forms of morphine sulfate may be identified by their X-ray powder diffraction peaks/pattern. X-ray powder diffraction analysis on representative samples of the crystalline forms of morphine sulfate as herein described is performed using a Bruker D8 Advance instrument equipped with a Cu Kα radiation source (1.54° Angstrom), a 9-position sample holder and a LYNXEYE™ Super Speed Detector. Samples are placed on zero-background, silicon plate holders. 
     One skilled in the art would recognize that the ° 2θ values and the relative intensity values are generated by performing a peak search on the measured data and the d-spacing values are calculated by the instrument from the ° 2θ values using Bragg&#39;s equation. One skilled in the art would further recognize that the relative intensity for the measured peaks may vary as a result of sample preparation, orientation and instrument used, for example. A variation of about ±0.2 is not atypical in obtainable 2θ values. 
     Morphine sulfate Form α is a unique crystalline phase. Morphine sulfate Form α may be characterized as a white to off-white powder. Morphine sulfate Form α is further characterized by its X-ray powder diffraction pattern peaks and/or d-spacing values, as listed in Table 1 below.  FIG. 2  is a representative X-ray powder diffractogram for a representative sample of morphine sulfate Form α made according to Examples 3 and 4. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 XRPD peak list of Form α 
               
            
           
           
               
               
               
               
               
            
               
                   
                 2θ 
                 d spacing, A° 
                 Count 
                 % 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 7.54 
                 11.721 
                 7785 
                 4.3 
               
               
                   
                 8.61 
                 10.268 
                 38031 
                 21.1 
               
               
                   
                 9.49 
                 9.312 
                 12778 
                 7.1 
               
               
                   
                 9.85 
                 8.973 
                 7574 
                 4.2 
               
               
                   
                 10.49 
                 8.429 
                 8583 
                 4.8 
               
               
                   
                 12.07 
                 7.328 
                 33865 
                 18.7 
               
               
                   
                 12.72 
                 6.954 
                 32689 
                 18.1 
               
               
                   
                 13.14 
                 6.735 
                 24265 
                 13.4 
               
               
                   
                 13.45 
                 6.576 
                 127441 
                 70.6 
               
               
                   
                 13.81 
                 6.405 
                 116666 
                 64.6 
               
               
                   
                 14.45 
                 6.125 
                 102448 
                 56.7 
               
               
                   
                 14.98 
                 5.908 
                 39629 
                 21.9 
               
               
                   
                 15.48 
                 5.721 
                 123015 
                 68.1 
               
               
                   
                 15.71 
                 5.635 
                 180619 
                 100 
               
               
                   
                 16.32 
                 5.429 
                 61348 
                 34 
               
               
                   
                 16.53 
                 5.360 
                 41019 
                 22.7 
               
               
                   
                 17.08 
                 5.187 
                 163643 
                 90.6 
               
               
                   
                 17.63 
                 5.026 
                 134116 
                 74.3 
               
               
                   
                 17.86 
                 4.964 
                 97291 
                 53.9 
               
               
                   
                 18.78 
                 4.721 
                 13223 
                 7.3 
               
               
                   
                 19.36 
                 4.581 
                 32796 
                 18.2 
               
               
                   
                 19.69 
                 4.506 
                 20822 
                 11.5 
               
               
                   
                 20.20 
                 4.394 
                 65519 
                 36.3 
               
               
                   
                 20.71 
                 4.286 
                 115491 
                 63.9 
               
               
                   
                 21.19 
                 4.190 
                 57204 
                 31.7 
               
               
                   
                 22.03 
                 4.032 
                 10157 
                 5.6 
               
               
                   
                 22.94 
                 3.874 
                 46005 
                 25.5 
               
               
                   
                 23.63 
                 3.762 
                 18021 
                 10 
               
               
                   
                 24.24 
                 3.669 
                 82081 
                 45.4 
               
               
                   
                 24.88 
                 3.575 
                 50940 
                 28.2 
               
               
                   
                 25.32 
                 3.514 
                 38533 
                 21.3 
               
               
                   
                 25.69 
                 3.466 
                 57300 
                 31.7 
               
               
                   
                 26.22 
                 3.396 
                 63972 
                 35.4 
               
               
                   
                 26.70 
                 3.336 
                 23001 
                 12.7 
               
               
                   
                 27.09 
                 3.289 
                 33408 
                 18.5 
               
               
                   
                 27.55 
                 3.235 
                 18065 
                 10 
               
               
                   
                 28.12 
                 3.171 
                 21428 
                 11.9 
               
               
                   
                 28.59 
                 3.120 
                 23902 
                 13.2 
               
               
                   
                 28.94 
                 3.083 
                 17979 
                 10 
               
               
                   
                 29.37 
                 3.039 
                 27704 
                 15.3 
               
               
                   
                 30.17 
                 2.960 
                 21079 
                 11.7 
               
               
                   
                 30.93 
                 2.889 
                 14141 
                 7.8 
               
               
                   
                 31.54 
                 2.834 
                 11195 
                 6.2 
               
               
                   
                 32.27 
                 2.772 
                 17448 
                 9.7 
               
               
                   
                 33.212 
                 2.69534 
                 11463 
                 6.3 
               
               
                   
                 33.974 
                 2.63664 
                 10917 
                 6 
               
               
                   
                 34.293 
                 2.61282 
                 12547 
                 6.9 
               
               
                   
                 35.837 
                 2.50371 
                 10904 
                 6 
               
               
                   
                 36.722 
                 2.4454 
                 16439 
                 9.1 
               
               
                   
                 37.636 
                 2.38808 
                 11620 
                 6.4 
               
               
                   
                 37.839 
                 2.37569 
                 11178 
                 6.2 
               
               
                   
                 39.62 
                 2.27295 
                 7555 
                 4.2 
               
               
                   
               
            
           
         
       
     
     Morphine sulfate Form β is a unique crystalline phase. Morphine sulfate Form β may be characterized as a white to off-white powder. Morphine sulfate Form β is further characterized by its X-ray powder diffraction pattern peaks and/or d-spacing values, as listed in Table 2 below.  FIG. 3  is a representative X-ray powder diffractogram for a representative sample of morphine sulfate Form β made according to Example 5. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 XRPD peak list of Form β 
               
            
           
           
               
               
               
               
               
            
               
                   
                 2θ 
                 d spacing, A° 
                 Count 
                 % 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 5.21 
                 16.962 
                 9073 
                 5 
               
               
                   
                 8.56 
                 10.322 
                 26160 
                 14.5 
               
               
                   
                 12.36 
                 7.156 
                 18702 
                 10.4 
               
               
                   
                 12.60 
                 7.020 
                 23369 
                 12.9 
               
               
                   
                 13.68 
                 6.468 
                 80427 
                 44.5 
               
               
                   
                 14.32 
                 6.178 
                 49082 
                 27.2 
               
               
                   
                 14.52 
                 6.094 
                 33095 
                 18.3 
               
               
                   
                 15.43 
                 5.738 
                 180661 
                 100 
               
               
                   
                 16.42 
                 5.394 
                 35816 
                 19.8 
               
               
                   
                 16.89 
                 5.246 
                 68594 
                 38 
               
               
                   
                 17.78 
                 4.984 
                 82044 
                 45.4 
               
               
                   
                 18.55 
                 4.779 
                 8643 
                 4.8 
               
               
                   
                 19.26 
                 4.605 
                 22015 
                 12.2 
               
               
                   
                 19.72 
                 4.499 
                 15094 
                 8.4 
               
               
                   
                 20.14 
                 4.406 
                 49433 
                 27.4 
               
               
                   
                 20.58 
                 4.313 
                 50985 
                 28.2 
               
               
                   
                 21.08 
                 4.212 
                 37666 
                 20.8 
               
               
                   
                 21.67 
                 4.097 
                 10205 
                 5.6 
               
               
                   
                 22.87 
                 3.886 
                 31679 
                 17.5 
               
               
                   
                 23.98 
                 3.709 
                 31482 
                 17.4 
               
               
                   
                 24.34 
                 3.653 
                 49142 
                 27.2 
               
               
                   
                 24.69 
                 3.603 
                 35649 
                 19.7 
               
               
                   
                 25.34 
                 3.512 
                 14993 
                 8.3 
               
               
                   
                 25.78 
                 3.453 
                 48874 
                 27.1 
               
               
                   
                 26.13 
                 3.407 
                 26087 
                 14.4 
               
               
                   
                 26.68 
                 3.339 
                 33491 
                 18.5 
               
               
                   
                 27.58 
                 3.232 
                 11169 
                 6.2 
               
               
                   
                 27.99 
                 3.185 
                 13749 
                 7.6 
               
               
                   
                 28.43 
                 3.136 
                 12380 
                 6.9 
               
               
                   
                 28.75 
                 3.102 
                 11857 
                 6.6 
               
               
                   
                 29.25 
                 3.051 
                 21413 
                 11.9 
               
               
                   
                 29.81 
                 2.995 
                 10374 
                 5.7 
               
               
                   
                 30.75 
                 2.906 
                 11393 
                 6.3 
               
               
                   
                 31.50 
                 2.837 
                 8816 
                 4.9 
               
               
                   
                 32.10 
                 2.786 
                 12678 
                 7 
               
               
                   
                 33.02 
                 2.710 
                 10467 
                 5.8 
               
               
                   
                 33.94 
                 2.639 
                 12603 
                 7 
               
               
                   
                 34.50 
                 2.598 
                 10964 
                 6.1 
               
               
                   
                 35.69 
                 2.513 
                 8555 
                 4.7 
               
               
                   
                 36.56 
                 2.456 
                 10659 
                 5.9 
               
               
                   
                   
               
            
           
         
       
     
     Morphine sulfate Form γ is a unique crystalline phase. Morphine sulfate Form γ may be characterized as a white to off-white powder. Morphine sulfate Form γ is further characterized by its X-ray powder diffraction pattern peaks and/or d-spacing values, as listed in Table 3 below.  FIG. 4  is a representative X-ray powder diffractogram for a representative sample of morphine sulfate Form γ made according to Example 6. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 XRPD peak list of Form γ 
               
            
           
           
               
               
               
               
               
            
               
                   
                 2θ 
                 d spacing, A° 
                 Count 
                 % 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 7.453 
                 11.852 
                 14058 
                 7.6 
               
               
                   
                 8.455 
                 10.450 
                 30831 
                 16.6 
               
               
                   
                 9.269 
                 9.534 
                 24458 
                 13.2 
               
               
                   
                 10.115 
                 8.738 
                 26802 
                 14.4 
               
               
                   
                 10.333 
                 8.554 
                 22449 
                 12.1 
               
               
                   
                 11.274 
                 7.842 
                 13683 
                 7.4 
               
               
                   
                 11.716 
                 7.547 
                 14746 
                 7.9 
               
               
                   
                 12.049 
                 7.340 
                 21602 
                 11.6 
               
               
                   
                 12.457 
                 7.100 
                 63642 
                 34.3 
               
               
                   
                 12.804 
                 6.908 
                 58128 
                 31.3 
               
               
                   
                 13.214 
                 6.695 
                 150759 
                 81.2 
               
               
                   
                 13.811 
                 6.407 
                 40814 
                 22 
               
               
                   
                 14.284 
                 6.195 
                 185710 
                 100 
               
               
                   
                 14.826 
                 5.970 
                 46595 
                 25.1 
               
               
                   
                 15.176 
                 5.834 
                 46458 
                 25 
               
               
                   
                 15.627 
                 5.666 
                 110758 
                 59.6 
               
               
                   
                 16.174 
                 5.476 
                 52472 
                 28.3 
               
               
                   
                 16.445 
                 5.386 
                 80017 
                 43.1 
               
               
                   
                 16.95 
                 5.227 
                 122648 
                 66 
               
               
                   
                 17.467 
                 5.073 
                 119559 
                 64.4 
               
               
                   
                 18.363 
                 4.828 
                 28359 
                 15.3 
               
               
                   
                 18.852 
                 4.703 
                 59796 
                 32.2 
               
               
                   
                 19.542 
                 4.539 
                 16054 
                 8.6 
               
               
                   
                 20.129 
                 4.408 
                 36101 
                 19.4 
               
               
                   
                 20.577 
                 4.313 
                 67254 
                 36.2 
               
               
                   
                 21.291 
                 4.170 
                 21516 
                 11.6 
               
               
                   
                 21.989 
                 4.039 
                 29706 
                 16 
               
               
                   
                 22.549 
                 3.940 
                 42588 
                 22.9 
               
               
                   
                 22.869 
                 3.885 
                 57195 
                 30.8 
               
               
                   
                 23.329 
                 3.810 
                 33391 
                 18 
               
               
                   
                 23.871 
                 3.725 
                 53918 
                 29 
               
               
                   
                 24.101 
                 3.690 
                 30277 
                 16.3 
               
               
                   
                 24.68 
                 3.604 
                 29904 
                 16.1 
               
               
                   
                 24.903 
                 3.573 
                 47681 
                 25.7 
               
               
                   
                 25.157 
                 3.537 
                 35556 
                 19.1 
               
               
                   
                 25.758 
                 3.456 
                 30234 
                 16.3 
               
               
                   
                 26.09 
                 3.413 
                 26587 
                 14.3 
               
               
                   
                 26.474 
                 3.364 
                 15218 
                 8.2 
               
               
                   
                 26.992 
                 3.301 
                 24641 
                 13.3 
               
               
                   
                 27.243 
                 3.271 
                 19820 
                 10.7 
               
               
                   
                 27.944 
                 3.190 
                 18586 
                 10 
               
               
                   
                 28.632 
                 3.115 
                 15926 
                 8.6 
               
               
                   
                 29.37 
                 3.039 
                 15433 
                 8.3 
               
               
                   
                 29.953 
                 2.981 
                 20227 
                 10.9 
               
               
                   
                 30.801 
                 2.901 
                 13006 
                 7 
               
               
                   
                 31.443 
                 2.843 
                 18739 
                 10.1 
               
               
                   
                   
               
            
           
         
       
     
     Morphine sulfate Form δ is a unique crystalline phase. Morphine sulfate Form δ may be characterized as a white to off-white powder. Morphine sulfate Form δ is further characterized by its X-ray powder diffraction pattern peaks and/or d-spacing values, as listed in Table 4 below.  FIG. 5  is a representative X-ray powder diffractogram for a representative sample of morphine sulfate Form δ made according to Example 7. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 XRPD peak list of Form δ 
               
            
           
           
               
               
               
               
               
            
               
                   
                 2θ 
                 d spacing, A° 
                 Count 
                 % 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 5.70 
                 15.486 
                 23544 
                 13.3 
               
               
                   
                 8.54 
                 10.344 
                 7313 
                 4.1 
               
               
                   
                 9.43 
                 9.368 
                 5049 
                 2.9 
               
               
                   
                 10.50 
                 8.416 
                 8086 
                 4.6 
               
               
                   
                 11.34 
                 7.799 
                 48561 
                 27.5 
               
               
                   
                 13.37 
                 6.615 
                 37282 
                 21.1 
               
               
                   
                 13.76 
                 6.432 
                 27356 
                 15.5 
               
               
                   
                 14.37 
                 6.159 
                 13851 
                 7.8 
               
               
                   
                 15.39 
                 5.754 
                 44927 
                 25.4 
               
               
                   
                 15.68 
                 5.646 
                 176656 
                 100 
               
               
                   
                 16.20 
                 5.466 
                 23125 
                 13.1 
               
               
                   
                 17.03 
                 5.203 
                 77012 
                 43.6 
               
               
                   
                 17.54 
                 5.051 
                 58036 
                 32.9 
               
               
                   
                 17.87 
                 4.961 
                 14950 
                 8.5 
               
               
                   
                 19.55 
                 4.537 
                 7832 
                 4.4 
               
               
                   
                 20.14 
                 4.406 
                 18108 
                 10.3 
               
               
                   
                 20.64 
                 4.299 
                 52029 
                 29.5 
               
               
                   
                 21.15 
                 4.198 
                 20217 
                 11.4 
               
               
                   
                 21.99 
                 4.03875 
                 10728 
                 6.1 
               
               
                   
                 22.427 
                 3.96113 
                 16914 
                 9.6 
               
               
                   
                 22.66 
                 3.92087 
                 16607 
                 9.4 
               
               
                   
                 24.001 
                 3.70482 
                 22324 
                 12.6 
               
               
                   
                 24.169 
                 3.6794 
                 24531 
                 13.9 
               
               
                   
                 24.873 
                 3.57683 
                 27399 
                 15.5 
               
               
                   
                 25.184 
                 3.53337 
                 17641 
                 10 
               
               
                   
                 25.71 
                 3.46233 
                 17253 
                 9.8 
               
               
                   
                 26.202 
                 3.39833 
                 51837 
                 29.3 
               
               
                   
                 26.659 
                 3.34116 
                 16594 
                 9.4 
               
               
                   
                 27.052 
                 3.2935 
                 41688 
                 23.6 
               
               
                   
                 27.477 
                 3.24353 
                 9229 
                 5.2 
               
               
                   
                 28.06 
                 3.17744 
                 8234 
                 4.7 
               
               
                   
                 28.488 
                 3.13069 
                 8906 
                 5 
               
               
                   
                 29.37 
                 3.03856 
                 15075 
                 8.5 
               
               
                   
                 30.03 
                 2.97327 
                 11893 
                 6.7 
               
               
                   
                 31.512 
                 2.83673 
                 6770 
                 3.8 
               
               
                   
                 32.238 
                 2.77452 
                 12699 
                 7.2 
               
               
                   
                 33.137 
                 2.70129 
                 5857 
                 3.3 
               
               
                   
                 34.866 
                 2.57114 
                 5473 
                 3.1 
               
               
                   
                 35.732 
                 2.51081 
                 5019 
                 2.8 
               
               
                   
                 36.913 
                 2.43317 
                 7795 
                 4.4 
               
               
                   
                 37.581 
                 2.39145 
                 8745 
                 5 
               
               
                   
                 38.562 
                 2.33282 
                 5063 
                 2.9 
               
               
                   
                 39.5 
                 2.27953 
                 5249 
                 3 
               
               
                   
                   
               
            
           
         
       
     
     Morphine sulfate Form ε is a unique crystalline phase. Morphine sulfate Form ε may be characterized as a white to off-white powder. Morphine sulfate Form ε is further characterized by its X-ray powder diffraction pattern peaks and/or d-spacing values, as listed in Table 5 below.  FIG. 6  is a representative X-ray powder diffractogram for a representative sample of morphine sulfate Form ε made according to Example 8. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 XRPD peak list of Form ε 
               
            
           
           
               
               
               
               
               
            
               
                   
                 2θ 
                 d spacing, A° 
                 Count 
                 % 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 9.59 
                 9.216 
                 49596 
                 27.5 
               
               
                   
                 10.80 
                 8.189 
                 58820 
                 32.6 
               
               
                   
                 11.03 
                 8.012 
                 28976 
                 16 
               
               
                   
                 12.01 
                 7.362 
                 10490 
                 5.8 
               
               
                   
                 12.41 
                 7.125 
                 8694 
                 4.8 
               
               
                   
                 13.54 
                 6.535 
                 56197 
                 31.1 
               
               
                   
                 14.40 
                 6.145 
                 180610 
                 100 
               
               
                   
                 14.98 
                 5.911 
                 7730 
                 4.3 
               
               
                   
                 15.79 
                 5.608 
                 15043 
                 8.3 
               
               
                   
                 16.44 
                 5.389 
                 54987 
                 30.4 
               
               
                   
                 16.67 
                 5.313 
                 30704 
                 17 
               
               
                   
                 17.22 
                 5.144 
                 4957 
                 2.7 
               
               
                   
                 17.78 
                 4.984 
                 3188 
                 1.8 
               
               
                   
                 18.77 
                 4.723 
                 32612 
                 18.1 
               
               
                   
                 19.20 
                 4.620 
                 56708 
                 31.4 
               
               
                   
                 19.92 
                 4.453 
                 16250 
                 9 
               
               
                   
                 20.38 
                 4.355 
                 36651 
                 20.3 
               
               
                   
                 21.42 
                 4.145 
                 21869 
                 12.1 
               
               
                   
                 22.01 
                 4.036 
                 50499 
                 28 
               
               
                   
                 22.59 
                 3.934 
                 5792 
                 3.2 
               
               
                   
                 22.94 
                 3.874 
                 7766 
                 4.3 
               
               
                   
                 23.58 
                 3.770 
                 121785 
                 67.4 
               
               
                   
                 24.29 
                 3.661 
                 5575 
                 3.1 
               
               
                   
                 24.87 
                 3.577 
                 13138 
                 7.3 
               
               
                   
                 25.44 
                 3.498 
                 9570 
                 5.3 
               
               
                   
                 26.08 
                 3.414 
                 16116 
                 8.9 
               
               
                   
                 26.73 
                 3.333 
                 8477 
                 4.7 
               
               
                   
                 27.10 
                 3.288 
                 5473 
                 3 
               
               
                   
                 27.78 
                 3.209 
                 7022 
                 3.9 
               
               
                   
                 28.09 
                 3.174 
                 17147 
                 9.5 
               
               
                   
                 28.66 
                 3.113 
                 13869 
                 7.7 
               
               
                   
                 28.87 
                 3.090 
                 15599 
                 8.6 
               
               
                   
                 29.73 
                 3.003 
                 18568 
                 10.3 
               
               
                   
                 30.35 
                 2.942 
                 6191 
                 3.4 
               
               
                   
                 31.08 
                 2.876 
                 7841 
                 4.3 
               
               
                   
                 31.87 
                 2.806 
                 4392 
                 2.4 
               
               
                   
                 32.82 
                 2.726 
                 6976 
                 3.9 
               
               
                   
                 33.03 
                 2.710 
                 8059 
                 4.5 
               
               
                   
                 33.48 
                 2.674 
                 8999 
                 5 
               
               
                   
                 34.77 
                 2.578 
                 13351 
                 7.4 
               
               
                   
                 36.18 
                 2.481 
                 3929 
                 2.2 
               
               
                   
                 36.93 
                 2.432 
                 5783 
                 3.2 
               
               
                   
                 37.50 
                 2.396 
                 8307 
                 4.6 
               
               
                   
                 37.93 
                 2.370 
                 4888 
                 2.7 
               
               
                   
                 38.76 
                 2.321 
                 4425 
                 2.4 
               
               
                   
                 39.26 
                 2.293 
                 3838 
                 2.1 
               
               
                   
                 39.72 
                 2.267 
                 3764 
                 2.1 
               
               
                   
                   
               
            
           
         
       
     
     Morphine sulfate Form ζ is a unique crystalline phase. Morphine sulfate Form ζ may be characterized as a white to off-white powder. Morphine sulfate Form ζ is further characterized by its X-ray powder diffraction pattern peaks and/or d-spacing values, as listed in Table 6 below.  FIG. 7  is a representative X-ray powder diffractogram for a representative sample of morphine sulfate Form ζ made according to Example 9. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 XRPD peak list of Form ζ 
               
            
           
           
               
               
               
               
               
            
               
                   
                 2θ 
                 d spacing, A° 
                 Count 
                 % 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 5.83 
                 15.145 
                 67066 
                 37.9 
               
               
                   
                 10.53 
                 8.397 
                 67455 
                 38.1 
               
               
                   
                 11.61 
                 7.613 
                 64699 
                 36.6 
               
               
                   
                 12.03 
                 7.353 
                 18553 
                 10.5 
               
               
                   
                 13.37 
                 6.617 
                 16740 
                 9.5 
               
               
                   
                 13.67 
                 6.475 
                 131887 
                 74.5 
               
               
                   
                 14.28 
                 6.198 
                 177010 
                 100 
               
               
                   
                 15.68 
                 5.646 
                 139905 
                 79 
               
               
                   
                 17.03 
                 5.203 
                 29597 
                 16.7 
               
               
                   
                 17.45 
                 5.078 
                 13720 
                 7.8 
               
               
                   
                 17.76 
                 4.989 
                 42869 
                 24.2 
               
               
                   
                 18.93 
                 4.685 
                 17523 
                 9.9 
               
               
                   
                 20.44 
                 4.342 
                 148314 
                 83.8 
               
               
                   
                 21.28 
                 4.173 
                 5956 
                 3.4 
               
               
                   
                 21.89 
                 4.056 
                 47000 
                 26.6 
               
               
                   
                 22.24 
                 3.995 
                 24366 
                 13.8 
               
               
                   
                 22.86 
                 3.888 
                 31247 
                 17.7 
               
               
                   
                 23.30 
                 3.815 
                 22223 
                 12.6 
               
               
                   
                 24.24 
                 3.668 
                 118902 
                 67.2 
               
               
                   
                 24.89 
                 3.575 
                 10814 
                 6.1 
               
               
                   
                 25.56 
                 3.482 
                 28441 
                 16.1 
               
               
                   
                 26.39 
                 3.374 
                 67762 
                 38.3 
               
               
                   
                 26.81 
                 3.323 
                 5745 
                 3.2 
               
               
                   
                 27.52 
                 3.239 
                 35467 
                 20 
               
               
                   
                 28.44 
                 3.136 
                 17251 
                 9.7 
               
               
                   
                 28.87 
                 3.091 
                 20379 
                 11.5 
               
               
                   
                 29.26 
                 3.049 
                 12317 
                 7 
               
               
                   
                 30.08 
                 2.968 
                 5088 
                 2.9 
               
               
                   
                 30.52 
                 2.927 
                 18570 
                 10.5 
               
               
                   
                 31.22 
                 2.862 
                 6028 
                 3.4 
               
               
                   
                 31.62 
                 2.827 
                 14302 
                 8.1 
               
               
                   
                 31.88 
                 2.805 
                 8467 
                 4.8 
               
               
                   
                 32.39 
                 2.762 
                 12007 
                 6.8 
               
               
                   
                 33.42 
                 2.679 
                 3102 
                 1.8 
               
               
                   
                 33.93 
                 2.640 
                 28295 
                 16 
               
               
                   
                 34.59 
                 2.591 
                 5340 
                 3 
               
               
                   
                 35.08 
                 2.556 
                 10972 
                 6.2 
               
               
                   
                 36.49 
                 2.460 
                 11523 
                 6.5 
               
               
                   
                 36.92 
                 2.433 
                 7022 
                 4 
               
               
                   
                 37.62 
                 2.389 
                 4998 
                 2.8 
               
               
                   
                 38.25 
                 2.351 
                 3796 
                 2.1 
               
               
                   
                 38.89 
                 2.314 
                 5009 
                 2.8 
               
               
                   
                 39.24 
                 2.294 
                 5205 
                 2.9 
               
               
                   
                 39.80 
                 2.263 
                 6548 
                 3.7 
               
               
                   
               
            
           
         
       
     
     Morphine sulfate Form η is a unique crystalline phase. Morphine sulfate Form η may be characterized as a white to off-white powder. Morphine sulfate Form η is further characterized by its X-ray powder diffraction pattern peaks and/or d-spacing values, as listed in Table 7 below.  FIG. 8  is a representative X-ray powder diffractogram for a representative sample of morphine sulfate Form η made according to Example 10. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 XRPD peak list of Form η 
               
            
           
           
               
               
               
               
               
            
               
                   
                 2θ 
                 d spacing, A° 
                 Count 
                 % 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 7.75 
                 11.405 
                 4463 
                 15 
               
               
                   
                 9.16 
                 9.643 
                 2920 
                 9.8 
               
               
                   
                 10.71 
                 8.258 
                 1812 
                 6.1 
               
               
                   
                 12.46 
                 7.100 
                 2817 
                 9.5 
               
               
                   
                 12.87 
                 6.875 
                 11111  
                 37.3 
               
               
                   
                 13.15 
                 6.727 
                 11390  
                 38.3 
               
               
                   
                 13.52 
                 6.545 
                 8090 
                 27.2 
               
               
                   
                 13.88 
                 6.374 
                 7809 
                 26.2 
               
               
                   
                 14.36 
                 6.162 
                 26492 
                 89 
               
               
                   
                 14.87 
                 5.952 
                 3086 
                 10.4 
               
               
                   
                 15.49 
                 5.717 
                 29771 
                 100 
               
               
                   
                 16.42 
                 5.394 
                 18857 
                 63.3 
               
               
                   
                 16.68 
                 5.311 
                 7777 
                 26.1 
               
               
                   
                 17.19 
                 5.156 
                 10816 
                 36.3 
               
               
                   
                 17.36 
                 5.103 
                 9882 
                 33.2 
               
               
                   
                 18.33 
                 4.835 
                 14720 
                 49.4 
               
               
                   
                 19.37 
                 4.580 
                 5087 
                 17.1 
               
               
                   
                 19.83 
                 4.473 
                 4094 
                 13.8 
               
               
                   
                 20.14 
                 4.405 
                 2502 
                 8.4 
               
               
                   
                 20.54 
                 4.320 
                 6772 
                 22.7 
               
               
                   
                 20.97 
                 4.234 
                 4808 
                 16.2 
               
               
                   
                 21.27 
                 4.175 
                 7703 
                 25.9 
               
               
                   
                 21.51 
                 4.128 
                 9621 
                 32.3 
               
               
                   
                 21.96 
                 4.045 
                 13770 
                 46.3 
               
               
                   
                 22.44 
                 3.959 
                 5453 
                 18.3 
               
               
                   
                 22.73 
                 3.909 
                 3857 
                 13 
               
               
                   
                 23.09 
                 3.848 
                 4832 
                 16.2 
               
               
                   
                 23.31 
                 3.813 
                 8138 
                 27.3 
               
               
                   
                 23.88 
                 3.723 
                 10490 
                 35.2 
               
               
                   
                 24.81 
                 3.585 
                 2936 
                 9.9 
               
               
                   
                 25.12 
                 3.542 
                 6737 
                 22.6 
               
               
                   
                 25.70 
                 3.463 
                 5827 
                 19.6 
               
               
                   
                 25.88 
                 3.440 
                 6250 
                 21 
               
               
                   
                 26.21 
                 3.397 
                 4614 
                 15.5 
               
               
                   
                 26.64 
                 3.344 
                 5066 
                 17 
               
               
                   
                 27.20 
                 3.276 
                 4950 
                 16.6 
               
               
                   
                 27.93 
                 3.192 
                 3596 
                 12.1 
               
               
                   
                 28.89 
                 3.088 
                 7990 
                 26.8 
               
               
                   
                 30.03 
                 2.974 
                 3414 
                 11.5 
               
               
                   
                 31.43 
                 2.844 
                 4953 
                 16.6 
               
               
                   
                 32.98 
                 2.713 
                 2238 
                 7.5 
               
               
                   
                 35.52 
                 2.525 
                 3025 
                 10.2 
               
               
                   
                 39.21 
                 2.296 
                 2068 
                 6.9 
               
               
                   
                   
               
            
           
         
       
     
     Morphine sulfate Form θ is a unique crystalline phase. Morphine sulfate Form θ may be characterized as a white to off-white powder. Morphine sulfate Form θ is further characterized by its X-ray powder diffraction pattern peaks and/or d-spacing values, as listed in Table 8 below.  FIG. 9  is a representative X-ray powder diffractogram for a representative sample of morphine sulfate Form θ made according to Example 11. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 XRPD peak list of Form θ 
               
            
           
           
               
               
               
               
               
            
               
                   
                 2θ 
                 d spacing, A° 
                 Count 
                 % 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 4.17 
                 4.172 
                 44.5 
                 0.1 
               
               
                   
                 4.27 
                 4.269 
                 36.4 
                 0.1 
               
               
                   
                 6.20 
                 6.197 
                 4012 
                 7.3 
               
               
                   
                 10.56 
                 10.556 
                 5607 
                 10.2 
               
               
                   
                 11.00 
                 11.001 
                 8375 
                 15.3 
               
               
                   
                 12.36 
                 12.359 
                 33350 
                 60.8 
               
               
                   
                 13.18 
                 13.180 
                 7125 
                 13 
               
               
                   
                 14.05 
                 14.050 
                 54408 
                 99.2 
               
               
                   
                 14.22 
                 14.215 
                 54834 
                 100 
               
               
                   
                 15.33 
                 15.328 
                 599 
                 1.1 
               
               
                   
                 15.81 
                 15.812 
                 4672 
                 8.5 
               
               
                   
                 16.26 
                 16.255 
                 28665 
                 52.3 
               
               
                   
                 16.90 
                 16.897 
                 15956 
                 29.1 
               
               
                   
                 17.73 
                 17.726 
                 13145 
                 24 
               
               
                   
                 18.72 
                 18.716 
                 5306 
                 9.7 
               
               
                   
                 19.03 
                 19.026 
                 9348 
                 17 
               
               
                   
                 20.12 
                 20.118 
                 828 
                 1.5 
               
               
                   
                 20.73 
                 20.733 
                 31446 
                 57.3 
               
               
                   
                 21.38 
                 21.376 
                 2555 
                 4.7 
               
               
                   
                 22.04 
                 22.037 
                 2930 
                 5.3 
               
               
                   
                 22.74 
                 22.742 
                 17287 
                 31.5 
               
               
                   
                 23.11 
                 23.109 
                 6983 
                 12.7 
               
               
                   
                 24.14 
                 24.138 
                 1040 
                 1.9 
               
               
                   
                 24.54 
                 24.538 
                 1670 
                 3 
               
               
                   
                 24.99 
                 24.990 
                 9728 
                 17.7 
               
               
                   
                 25.25 
                 25.247 
                 13894 
                 25.3 
               
               
                   
                 25.56 
                 25.561 
                 5572 
                 10.2 
               
               
                   
                 25.92 
                 25.923 
                 15440 
                 28.2 
               
               
                   
                 26.50 
                 26.496 
                 2590 
                 4.7 
               
               
                   
                 27.40 
                 27.402 
                 1552 
                 2.8 
               
               
                   
                 27.75 
                 27.752 
                 4031 
                 7.4 
               
               
                   
                 28.03 
                 28.025 
                 3130 
                 5.7 
               
               
                   
                 28.59 
                 28.592 
                 6237 
                 11.4 
               
               
                   
                 29.34 
                 29.335 
                 1363 
                 2.5 
               
               
                   
                 29.98 
                 29.979 
                 2835 
                 5.2 
               
               
                   
                 30.85 
                 30.848 
                 2642 
                 4.8 
               
               
                   
                 31.12 
                 31.121 
                 4001 
                 7.3 
               
               
                   
                 31.96 
                 31.961 
                 1156 
                 2.1 
               
               
                   
                 32.82 
                 32.815 
                 2220 
                 4 
               
               
                   
                 33.55 
                 33.549 
                 2879 
                 5.3 
               
               
                   
                 34.52 
                 34.515 
                 634 
                 1.2 
               
               
                   
                 35.48 
                 35.477 
                 1388 
                 2.5 
               
               
                   
                 36.01 
                 36.005 
                 2078 
                 3.8 
               
               
                   
                 36.75 
                 36.752 
                 441 
                 0.8 
               
               
                   
                 37.65 
                 37.653 
                 1361 
                 2.5 
               
               
                   
                 38.53 
                 38.534 
                 475 
                 0.9 
               
               
                   
                 39.84 
                 39.838 
                 946 
                 1.7 
               
               
                   
                   
               
            
           
         
       
     
     Differential scanning calorimetry is performed using a TA Instruments Q10 DSC. Typically, samples are placed in unsealed, covered hermetic alodined aluminum sample pans and scanned from about 30° C. to about 300° C. at a rate of about 10° C./min under a nitrogen purge of about 50 mL/min. 
     Differential scanning calorimetry is performed on representative samples of morphine sulfate Forms α, β, γ, δ, ε, ζ, η and θ, as shown in  FIGS. 11, 12, 13, 14, 15, 16, 17 and 18 , respectively. Two thermal events may be observed in the differential scanning calorimetry thermogram for morphine sulfate Form α at about 117° C. and about 173° C. Two thermal events may be observed in the differential scanning calorimetry thermogram for morphine sulfate Form β at about 112° C. and about 177° C. Two thermal events may be observed in the differential scanning calorimetry thermogram for morphine sulfate Form γ at about 140° C. and about 234° C. Three thermal events may be observed in the differential scanning calorimetry thermogram for morphine sulfate Form δ at about 58° C., 136° C. and about 221° C. One thermal event may be observed in the differential scanning calorimetry thermogram for morphine sulfate Form ε at about 160° C. Two thermal events may be observed in the differential scanning calorimetry thermogram for morphine sulfate Form ζ at about 163° C. and about 238° C. One thermal event may be observed in the differential scanning calorimetry thermogram for morphine sulfate Form η at about 284° C. Two thermal events may be observed in the differential scanning calorimetry thermogram for morphine sulfate Form θ at about 158° C. and about 237° C. 
     The present disclosure also describes pharmaceutical compositions comprising one or more of the morphine sulfate crystalline forms as herein described in association with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances. These compositions may be in dosage forms such as, but not limited to, tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. 
     To prepare a pharmaceutical composition of the present disclosure, any one or more of the morphine sulfate crystalline forms as herein described is intimately admixed with a pharmaceutical excipient according to conventional pharmaceutical compounding techniques, which excipient may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable excipients include those known in the art and those yet to be discovered. Descriptions of some of these pharmaceutically acceptable excipients may be found in  The Handbook of Pharmaceutical Excipients  and the Pharmaceutical Society of Great Britain. The pharmaceutical compositions of the present disclosure may be prepared according to any method known in the art as well as yet to be discovered improvements thereto. Methods of formulating pharmaceutical compositions have been described in numerous publications such as  Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded , Volumes 1-3 ; Pharmaceutical Dosage Forms: Parenteral Medications , Volumes 1-2; and  Pharmaceutical Dosage Forms: Disperse Systems , Volumes 1-2. 
     The oral formulations of the present disclosure may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. The sustained release dosage forms may optionally comprise particles containing any one or more of the morphine sulfate forms as herein described. Preferably, the particles are film coated with a material that permits release of the active at a sustained rate in an aqueous medium. The film coat is chosen so as to achieve, in combination with the other stated properties, desired release properties. The sustained release coating formulations of the present disclosure should preferably be capable of producing a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert and tack-free. The sustained release formulations of the present disclosure preferably slowly release the active agent(s), e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. Sustained release dosage forms according to the present disclosure may also be prepared as osmotic dosage formulations known in the art as well as improvements thereto. 
     The liquid forms in which the novel compositions of the present disclosure may be incorporated for administration orally or by injectable include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils as well as elixirs and similar pharmaceutical vehicles. The liquid forms may include suitably flavored suspending or dispersing agents such as the synthetic and natural gums. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservative are employed when intravenous administration is desired. 
     The formulations of the present disclosure may be formulated as a pharmaceutical suppository for rectal administration comprising a suitable suppository base, and any one or more of the morphine sulfate crystalline forms as herein described. This includes the preparation of sustained release suppository formulations as described in U.S. Pat. No. 5,215,758. 
     The compounds of the present disclosure may be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will be continuous rather than intermittent throughout the dosage regimen. 
     The present disclosure provides for a method of treating pain by administering to a subject in need thereof the dosage forms described above which contain any one or more of the morphine sulfate crystalline forms as herein described. The dosage of the products may be varied over a wide range. Optimal dosages and dosage regimens to be administered may be readily determined by those skilled in the art, and will vary with the mode of administration, the strength of the preparation and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject&#39;s sex, age, weight, diet, physical activity, time of administration and concomitant diseases, will result in the need to adjust dosages and/or regimens. 
     EXAMPLES 
     The disclosure is illustrated by the following examples. 
     The following examples are set forth to aid in the understanding of the disclosure, and are not intended and should not be construed to limit in any way the disclosure set forth in the claims which follow thereafter. Although illustrated and herein described with reference to certain specific embodiments, the present disclosure is nevertheless not intended to be limited to the details shown. Rather, various modifications may be made in the details within the scope and range of equivalents of the claims and without departing from the spirit of the disclosure. 
     Example 1 
     Preparation of Morphine Sulfate 
     Morphine Technical Alkaloid (MTA) material is combined with water and 0.5 equiv. of 50% isopropyl acetate diluted sulfuric acid. The mixture is heated to about 75° C. and cooled to about 15° C. at a rate of about 0.23° C. per minute. The resulting mixture is filtered under vacuum and washed with ethanol. The filtrate is dried at about 50° C. under vacuum. The resulting solids are determined to be morphine sulfate. 
     Example 2 
     Preparation of Morphine Free Base 
     About 8.43 g of morphine sulfate and about 40 mL of water are added to an Easy Max™ set at 350 RPM agitation rate. The mixture becomes clear and is then heated to about 65° C. The pH is checked and determined to be about 5. About 10 mL of pre-made solution in water of 1 M NaOH is added to the mixture. Solids are formed. About 5 mL of pre-made solution in water of 1 M NaOH is added to the mixture. The pH is checked and determined to be about 6. A few NaOH pellets are added to the mixture. Heating and stirring is continued for about 2 hours. The mixture is then cooled to about 50° C., filtered under vacuum filtration and washed several times with water. The pH of the filtrate is checked and determined to be about 13. The filtrate is dried at about 45° C. under vacuum for about 12-24 hours. The resulting solids are analyzed by X-ray powder diffraction and determined to be morphine free base. 
     Example 3 
     Preparation of Form α Using Acetone 
     About 200 mg of morphine free base and about 1 mL of acetone are added to a vial. Concentrated sulfuric acid is pre-diluted in isopropanol. About 49 μL of 50% isopropyl acetate diluted sulfuric acid is added to the vial. The mixture is stirred for about 4 to 5 hours at about 20 to 26° C. The resulting slurry is analyzed by X-ray powder diffraction and determined to be morphine sulfate Form α. 
     Example 4 
     Preparation of Form α Using Water 
     About 200 mg of morphine free base and about 1 mL of water are added to a vial. Concentrated sulfuric acid is pre-diluted in isopropanol. About 49 μL of 50% isopropyl acetate diluted sulfuric acid is added to the vial. The mixture is stirred for about 4 to 5 hours at about 55 to 65° C. The resulting solids are analyzed by X-ray powder diffraction and determined to be morphine sulfate Form α. 
     Example 5 
     Preparation of Form β Using Isopropyl Acetate 
     About 200 mg of morphine free base and about 1 mL of isopropyl acetate are added to a vial. Concentrated sulfuric acid is pre-diluted in isopropanol. About 49 μL of 50% isopropyl acetate diluted sulfuric acid is added to the vial. The mixture is stirred for about 4 to 5 hours at about 20 to 26° C. The resulting solids are analyzed by X-ray powder diffraction and determined to be morphine sulfate Form β. 
     Example 6 
     Preparation of Form γ Using Acetone 
     About 200 mg of morphine free base and about 1 mL of acetone are added to a vial. Concentrated sulfuric acid is pre-diluted in isopropanol. About 49 μL of 50% isopropyl acetate diluted sulfuric acid is added to the vial. The mixture is stirred for about 4 to 5 hours at about 55 to 65° C. The resulting solids are analyzed by X-ray powder diffraction and determined to be morphine sulfate Form γ. 
     Example 7 
     Preparation of Form δ Using Ethanol 
     About 200 mg of morphine free base and about 1 mL of ethanol are added to a vial. Concentrated sulfuric acid is pre-diluted in isopropanol. About 49 μL of 50% isopropyl acetate diluted sulfuric acid is added to the vial. The mixture is stirred for about 4 to 5 hours at about 20 to 26° C. The resulting solids are analyzed by X-ray powder diffraction and determined to be morphine sulfate Form δ. 
     Example 8 
     Preparation of Form ε Using Methanol 
     About 200 mg of morphine free base and about 1 mL of methanol are added to a vial. Concentrated sulfuric acid is pre-diluted in isopropanol. About 49 μL of 50% isopropyl acetate diluted sulfuric acid is added to the vial. The mixture is stirred for about 4 to 5 hours at about 20 to 26° C. The resulting solids are analyzed by X-ray powder diffraction and determined to be morphine sulfate Form ε. 
     Example 9 
     Preparation of Form ζ Using Water 
     About 200 mg of morphine free base and about 1 mL of water are added to a vial. Concentrated sulfuric acid is pre-diluted in isopropanol. About 49 μL of 50% isopropyl acetate diluted sulfuric acid is added to the vial. The mixture is stirred for about 4 to 5 hours at about 20 to 26° C. The resulting solids are analyzed by X-ray powder diffraction and determined to be morphine sulfate Form ζ. 
     Example 10 
     Preparation of Form η Using Ethanol/Methanol 
     About 200 mg of morphine free base and about 1 mL of ethanol/methanol 80:20 are added to a vial. Concentrated sulfuric acid is pre-diluted in isopropanol. About 49 μL of 50% isopropyl acetate diluted sulfuric acid is added to the vial. The mixture is stirred for about 4 to 5 hours at about 20 to 26° C. The resulting solids are analyzed by X-ray powder diffraction and determined to be morphine sulfate Form η. 
     Example 11 
     Preparation of Form θ Using Water 
     About 5 mg of MTA material, about 11 mL of water and a 50% solution of about 0.7 sulfuric acid equiv. are heated to about 70° C. The mixture is cooled at a rate of about 1.05° C. per minute with fast agitation (about 800 RPM) over about 2.5 hours. The resulting solids are analyzed by X-ray powder diffraction and determined to be morphine sulfate Form θ.