Abstract:
A process for acoustically mixing a bulk drug substance involves the application of acoustic energy to drive an accelerative force in a mixing vessel containing the drug substance. The drug substance may be, for example, Elagolix.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims the benefit of priority under 35 U.S.C. §119 of U.S. Provisional Application 62/189,677, filed Jul. 7, 2015, which is incorporated herein by reference in its entirety. 
     
    
     BACKGROUND 
       [0002]    Acoustic mixing technology has recently been introduced as an alternative mixing technology for powders and liquids that allows for rapid, uniform dispersion of material. This process operates on the principle of resonance where low frequency, acoustic energy creates a homogenous shear field within a mixing vessel, and the energy is transferred directly to the material to produce a consistent mixture without impellers or other additional mixing aids. This technology has been successfully applied to dry powder coating of drug particles having small particle size. The dry powder coating is often accomplished by co-mixing with nanosized inert substances such as SiO 2  where the admixture has improved surface properties resulting in improved processability. However, significantly less is known about the effect of acoustic mixing technology on drug particles having small size without the use of a co-additive such as SiO 2 . Described herein is the discovery that certain pharmaceutical products can be acoustically granulated without additional additives such as SiO 2  or other granulation aids (such as water and polymeric binders), leading to substantially improved drug properties and processability. This discovery represents a significant advance in the arts of dry powder formulation for particularly challenging drug substances as it does not require co-milling with inert(s) nor acoustic mixing with such inert(s). 
       SUMMARY 
       [0003]    In certain embodiments, this present disclosure comprises a process of acoustically mixing a bulk drug substance wherein said drug substance is substantially free of pharmaceutical excipients. 
         [0004]    In embodiments, the acoustic mixing comprises the application of acoustic waves sufficient to subject the mixing vessel containing the drug substance to an accelerative force of greater than 10G. 
         [0005]    For example, in embodiments, the G-force is greater than 20G, or greater than 30G, or 40G, or 50G, or 60G, or 70G, or 80G, or 90G, or 100G, or between 50G and 100G, or between 60G and 90 G, or between 60G and 80G, or about 77G, or about 85G. 
         [0006]    In embodiments, the G-force is greater than 20G. 
         [0007]    In embodiments, the G-force is greater than 30G. 
         [0008]    In embodiments, the G-force is greater than 40G. 
         [0009]    In embodiments, the G-force is greater than 50G. 
         [0010]    In embodiments, the G-force is greater than 60G. 
         [0011]    In embodiments, the G-force is greater than 70G. 
         [0012]    In embodiments, the G-force is greater than 80G. 
         [0013]    In embodiments, the G-force is greater than 90G. 
         [0014]    In embodiments, the G-force is greater than 100G. 
         [0015]    In embodiments, the G-force is between 50G and 100G. 
         [0016]    In embodiments, the G-force is between 60G and 80G. 
         [0017]    In embodiments, the G force is about 77G. 
         [0018]    In embodiments, the G-force is about 85G. 
         [0019]    In certain embodiments, said drug substance comprises an amorphous solid. In some embodiments, said drug substance comprises at least 50% w/w of an amorphous solid. 
         [0020]    In some embodiments, said drug substance comprises at least 75% of an amorphous solid. 
         [0021]    In some embodiments, said drug substance comprises at least 90% of an amorphous solid. 
         [0022]    In some embodiments, said drug substance comprises at least 95% of an amorphous solid. 
         [0023]    In some embodiments, said drug substance comprises at least 99% of an amorphous solid. 
         [0024]    In some embodiments, said drug substance comprises at least 99.5% of an amorphous solid. 
         [0025]    In certain embodiments, prior to acoustic mixing, the drug substance has a flowability constant (ffc) of less than 5. 
         [0026]    In certain embodiments, prior to acoustic mixing, the drug substance has a flowability constant (ffc) of less than 2. 
         [0027]    In certain embodiments, prior to acoustic mixing, the drug substance has a flowability constant (ffc) of between 2 and 0.3. 
         [0028]    In some embodiments, prior to acoustic mixing, the drug substance has a bulk density of less than 0.4 g/mL. 
         [0029]    In some embodiments, prior to acoustic mixing, the drug substance has a bulk density of less than 0.3 g/mL. 
         [0030]    In some embodiments, prior to acoustic mixing, the drug substance has a bulk density of less than 0.2 g/mL. 
         [0031]    In some embodiments, prior to acoustic mixing, the drug substance has a bulk density of between 0.2 g/ml and 0.05 g/ml. 
         [0032]    In embodiments, prior to acoustic mixing, the drug substance has a bulk density of from between less than 0.3 g/mL and more than 0.05 g/mL. 
         [0033]    In embodiments, acoustic mixing according to the instant disclosure increases the bulk density of the drug substance by at least 0.05 g/mL, such as at least 0.07 g/mL, or at least 0.1 g/mL, or at least 0.15 g/mL, or at least 0.16 g/mL, or at least 0.17 g/mL, or at least 0.18 g/mL, or at least 0.19 g/mL, or at least 0.2 g/mL, or at least 0.3 g/mL, or at least 0.4 g/mL, or at least 0.5 g/mL. For example, in embodiments, following acoustic mixing according to the instant disclosure, the bulk density of the drug substance is increased by an amount within the range of from about 0.03 to about 0.7, such as from about 0.04 to about 0.6, or from about 0.05 to about 0.2 g/mL, or from about 0.07 to about 0.19 g/mL, or about 0.1 to about 0.15 g/mL. For example, in embodiments, after acoustic mixing, the drug substance has a bulk density of from 0.2 to about 0.5 g/mL, such as from about 0.22 to about 0.35 g/mL, or from about 0.24 to about 0.3 g/mL. In embodiments, after acoustic mixing, the drug substance has a bulk density of greater than about 0.2 g/mL, such as greater than about 0.25 g/mL, or greater than about 0.3 g/mL. 
         [0034]    In embodiments, acoustic mixing according to the instant disclosure increases the bulk density of the drug substance by at least 10% relative to the initial bulk density of the drug substance (prior to acoustic mixing). In embodiments, acoustic mixing according to the instant disclosure increases the bulk density of the drug substance by at least 20% relative to the initial bulk density prior to mixing. In embodiments, acoustic mixing according to the instant disclosure increases the bulk density of the drug substance by 30% relative to the initial bulk density of the drug substance prior to acoustic mixing. In embodiments, acoustic mixing according to the instant disclosure increases the bulk density of the drug substance by 40% relative to the initial bulk density of the drug substance prior to acoustic mixing. In embodiments, acoustic mixing according to the instant disclosure increases the bulk density of the drug substance by 50% relative to the initial bulk density of the drug substance prior to acoustic mixing. In embodiments, acoustic mixing according to the instant disclosure increases the bulk density of the drug substance by 60% relative to the initial bulk density of the drug substance prior to acoustic mixing. In embodiments, acoustic mixing according to the instant disclosure increases the bulk density of the drug substance by 70% relative to the initial bulk density of the drug substance prior to acoustic mixing. In embodiments, acoustic mixing according to the instant disclosure increases the bulk density of the drug substance by 80% relative to the initial bulk density of the drug substance prior to acoustic mixing. In embodiments, acoustic mixing according to the instant disclosure increases the bulk density of the drug substance by 90% relative to the initial bulk density of the drug substance prior to acoustic mixing. In embodiments, acoustic mixing according to the instant disclosure increases the bulk density of the drug substance by 100% relative to the initial bulk density of the drug substance prior to acoustic mixing. In embodiments, acoustic mixing increases the bulk density of the drug substance by 200% relative to the initial bulk density. In embodiments, acoustic mixing increases the bulk density of the drug substance by 300% relative to the initial bulk density. For example, in embodiments, acoustic mixing according to the instant disclosure raises the bulk density of the drug substance from about 25% to about 150% relative to the initial bulk density prior to mixing, such as from about 30% to about 125%, or from about 40% to about 110% relative to the initial bulk density prior to mixing. 
         [0035]    In certain embodiments, prior to acoustic mixing, the drug substance has a volume-averaged particle size DV10 of less than 100. The term “particle size” refers, for example, to the size of a particle or agglomeration of particles. 
         [0036]    In certain embodiments, prior to acoustic mixing, the drug substance has a volume-averaged particle size DV10 of less than 50. 
         [0037]    In certain embodiments, prior to acoustic mixing, the drug substance has a volume-averaged particle size DV10 of less than 20. 
         [0038]    In certain embodiments, acoustic mixing of the drug substance increases the volume-averaged particle size DV10 by at least 10 um. 
         [0039]    In certain embodiments, acoustic mixing of the drug substance increases the volume-averaged particle size DV10 by at least 25 um. 
         [0040]    In certain embodiments, acoustic mixing of the drug substance increases the volume-averaged particle size DV10 by at least 50 um. 
         [0041]    In certain embodiments, acoustic mixing of the drug substance increases the volume-averaged particle size DV10 by at least 100 um. 
         [0042]    In certain embodiments, acoustic mixing of the drug substance increases the volume-averaged particle size DV10 by at least 150 um. 
         [0043]    In certain embodiments, acoustic mixing of the drug substance increases the volume-averaged particle size DV10 by at least 200 um. 
         [0044]    In certain embodiments, prior to acoustic mixing, the drug substance has a flowability constant (flow function coefficient, or ffc) of less than 3 and subsequent to mixing greater than 3. 
         [0045]    In certain embodiments, prior to acoustic mixing, the drug substance has a flowability constant (ffc) of less than 2 and subsequent to mixing greater than 2. 
         [0046]    In certain embodiments, prior to acoustic mixing, the drug substance has a flowability constant (ffc) of less than 1 and subsequent to mixing greater than 1. 
         [0047]    In some embodiments, acoustic mixing increases the flowability constant (ffc) by at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.5, 2.0, 2.5, 4.0, 7, 10, 12, or 15. 
         [0048]    In embodiments, the flowability constant is increased by at least 0.1. 
         [0049]    In embodiments, the flowability constant is increased by at least 0.2. 
         [0050]    In embodiments, the flowability constant is increased by at least 0.3 
         [0051]    In embodiments, the flowability constant is increased by at least 0.4. 
         [0052]    In embodiments, the flowability constant is increased by at least 0.5. 
         [0053]    In embodiments, the flowability constant is increased by at least 0.6 
         [0054]    In embodiments, the flowability constant is increased by at least 0.7 
         [0055]    In embodiments, the flowability constant is increased by at least 0.8 
         [0056]    In embodiments, the flowability constant is increased by at least 0.9. 
         [0057]    In embodiments, the flowability constant is increased by at least 1. 
         [0058]    In embodiments, the flowability constant is increased by at least 1.1. 
         [0059]    In embodiments, the flowability constant is increased by at least 1.2. 
         [0060]    In embodiments, the flowability constant is increased by at least 1.5. 
         [0061]    In embodiments, the flowability constant is increased by at least 2.0. 
         [0062]    In embodiments, the flowability constant is increased by at least 2.5. 
         [0063]    In embodiments, the flowability constant is increased by at least 4.0. 
         [0064]    In embodiments, the flowability constant is increased by at least 7. 
         [0065]    In embodiments, the flowability constant is increased by at least 10. 
         [0066]    In embodiments, the flowability constant is increased by at least 12. 
         [0067]    In embodiments, the flowability constant is increased by at least 15. 
         [0068]    In certain embodiments, said drug substance is Elagolix. 
         [0069]    In some embodiments, said drug substance is the mono-sodium salt of Elagolix. 
     
    
     
       DESCRIPTION OF THE FIGURES 
         [0070]      FIG. 1A  shows the chemical structure of Elagolix. 
           [0071]      FIG. 1B  shows the chemical structure of the mono-sodium salt of Elagolix. 
       
    
    
     DETAILED DESCRIPTION 
       [0072]    The process according to the instant disclosure can significantly improve the material properties of a drug substance (i.e., a compound suitable for pharmaceutical purposes without the admixture of additional excipients), such as powder flow and handling with respect to the development of electrostatic charge. The ResonantAcoustic® mixing technology employed in this disclosure utilizes resonance phenomenon to efficiently transfer energy to the particles inside the vessel, leading to rapid fluidization of drug substance particles. The high velocity of the particles, the frequent collisions among the particles, and collisions between the particles and the vessel result in the granulation of the drug substance (i.e., size enlargement). This is similar to observations typical during a granulation process which require binders and granulation fluids. This disclosure is the first demonstration of an auto-granulation process using the ResonantAcoustic® mixing technology. The additional benefit of such improvements on drug substance properties is the ability to develop formulations with increased processability due to enhanced flow and/or larger particle size. 
         [0073]    As used herein, the term “bulk drug substance” refers to a drug substance consisting of at least 90% w/w of the drug with no more than 10% w/w of pharmaceutical excipients or other materials. More specifically, bulk drug substance consists of at least 95% w/w drug substance with no more than 5% w/w of pharmaceutical excipients. Finally, the bulk substance consists of at least 99% w/w of drug substance with no more than 1% w/w of pharmaceutical excipients. 
         [0074]    The following examples are being submitted to illustrate embodiments of the present disclosure. This disclosure is not to be limited to its representative examples. Parts and percentages are by weight unless otherwise indicated. 
       EXAMPLES 
       [0075]    Elagolix drug substance was employed as an amorphous and hygroscopic solid having poor flowability (ffc&lt;2), and low bulk density (&lt;0.25 g/mL) and a variable particle size distribution due to the agglomeration of sub-micron primary particles. 
         [0076]    ResonantAcoustic® mixing technology has recently been introduced as an alternative mixing technology for powders and liquids that allows for rapid, uniform dispersion of material. This process operates on the principle of resonance where low frequency, acoustic energy creates a homogenous shear field within a mixing vessel, and the energy is transferred directly to the material to produce a consistent mixture without impellers or other additional mixing aids (Mullarney, M. P.; Beach, L. E.; Langdon, B. A.; Polizzi, M. A.,  Pharmaceutical Technology,  2011, 35, 94-102). 
       Example 1 
       [0077]    The feasibility of using acoustic mixing to improve the poor flow of Elagolix drug substance was assessed using a lab scale ResonantAcoustic® Mixer by varying the intensity and time of mixing. Mixing of neat Elagolix at 60% intensity up to 20 min and 80% up to 10 min resulted in large spherical granules, typical to what is observed during a wet granulation process. The intensity of mixing correlates with the accelerative force applied to the mixing vessel and a fortiori, the drug substance. Results shown in Table 1 demonstrate significant improvement in the flow properties of the drug substance. The greatest improvement in flow from ffc of 1.96 to 7.27 occurs after acoustic mixing at 80% intensity for 10 min, resulting in changing poor flowing material to free flowing material. 
         [0078]    Procedure—Dispense Elagolix sodium salt ( FIG. 1B ) drug substance in the acoustic mixing container sufficient to occupy a 50-80% fill volume. Allow the container to mix for the time periods indicated in the Table 1. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Particle Size and Flow of Elagolix 
               
               
                 before and after Acoustic Mixing 
               
             
          
           
               
                   
                 Run Intensity 
                 Run Time 
                   
                   
                   
                   
               
               
                 Run ID 
                 (%) 
                 (min) 
                 Dv10 
                 Dv50 
                 Dv90 
                 ffc 
               
               
                   
               
             
          
           
               
                 As is 
                 N/A 
                 N/A 
                 21 
                 337 
                 815 
                 1.96 
               
               
                 1 
                 40 
                 8 
                 154 
                 432 
                 939 
                 2.50 
               
               
                 2 
                 40 
                 16 
                 144 
                 405 
                 853 
                 2.10 
               
               
                 3 
                 60 
                 4 
                 143 
                 383 
                 842 
                 2.40 
               
               
                 4 
                 60 
                 8 
                 112 
                 298 
                 720 
                 2.80 
               
               
                 5 
                 60 
                 16 
                 270 
                 469 
                 795 
                 3.96 
               
               
                 6 
                 80 
                 6 
                 237 
                 512 
                 954 
                 3.21 
               
               
                 7 
                 80 
                 10 
                 281 
                 629 
                 1030 
                 7.27 
               
               
                   
               
             
          
         
       
     
       Example 2 
       [0079]    The feasibility of using acoustic mixing to improve the poor flow of Elagolix drug substance was assessed using a lab scale Resodyn® Acoustic Mixer (LamRAM II) by varying the fill level, mixing time, and mixing intensity. 
         [0080]    Procedure: Dispense Elagolix sodium salt drug substance in the acoustic mixing container sufficient to occupy the fill volume indicated below in Table 2. Allow the container to mix for the time period indicated in Table 2. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Physical Properties of Elagolix Before and After Acoustic Mixing 
               
             
          
           
               
                 Mixing 
                   
                   
                 Bulk 
                   
                   
               
               
                 Time 
                 % 
                 Force 
                 Density 
                 Flow 
                 Particle Size Distribution 
               
             
          
           
               
                 (min) 
                 Fill 
                 (G) 
                 (g/mL) 
                 (FFC) 
                 D(10) 
                 D(50) 
                 D(90) 
               
               
                   
               
             
          
           
               
                 0 
                 0 
                 0 
                 0.176 
                   
                   
                   
                   
               
               
                 15 
                 75 
                 60 
                 0.246 
                 2.1 
                 46.8 
                 156 
                 446 
               
               
                 15 
                 75 
                 70 
                 0.278 
                 2.8 
                 62.2 
                 181 
                 466 
               
               
                 15 
                 75 
                 85 
                 0.303 
                 3.6 
                 72.7 
                 161 
                 399 
               
               
                 30 
                 75 
                 60 
                 0.275 
                 2.5 
                 55.5 
                 154 
                 375 
               
               
                 30 
                 75 
                 70 
                 0.306 
                 3.6 
                 74.1 
                 164 
                 393 
               
               
                 30 
                 75 
                 85 
                 0.327 
                 5.6 
                 90.6 
                 153 
                 278 
               
               
                 15 + 15 
                 75 
                 85 
                 0.334 
                 5.1 
                 92.1 
                 155 
                 274 
               
               
                 30 
                 75 
                 100 
                 0.337 
                 5.1 
                 102 
                 156 
                 250 
               
               
                 30 
                 20 
                 85 
                 0.331 
                 5.1 
                 80.6 
                 141 
                 257 
               
               
                 30 
                 100 
                 85 
                 0.367 
                 7.5 
                 137 
                 229 
                 402 
               
               
                 45 
                 75 
                 60 
                 0.296 
                 3.6 
                 70.3 
                 166 
                 386 
               
               
                 45 
                 75 
                 70 
                 0.318 
                 4.9 
                 80.2 
                 156 
                 349 
               
               
                 45 
                 75 
                 85 
                 0.335 
                 5.5 
                 93.5 
                 145 
                 241 
               
               
                 60 
                 75 
                 60 
                 0.309 
                 4.2 
                 77.6 
                 172 
                 400 
               
               
                 60 
                 75 
                 70 
                 0.326 
                 5.3 
                 81.3 
                 146 
                 289 
               
               
                 60 
                 75 
                 85 
                 0.35 
                 5.4 
                 95.8 
                 149 
                 236