Screening For Solid Forms By Ultrasound Crystallization And Cocrystallization Using Ultrasound

Abstract

The present disclosure relates to crystallizing a chemical substance(s) using ultrasound. Methods are provided for screening a chemical substance according to its solid forms by using ultrasound to generate new or unusual solid forms. Methods are also provided for crystallizing a chemical substance by novel techniques that include sonication. The present disclosure also relates to cocrystallization using ultrasound. Methods are provided for preparing cocrystals of an active agent and a guest by sonicating and crystallizing. Methods are also provided for screening a sample according to solid state phases (such as cocrystals and salts) and include generating a cocrystal from the sample using ultrasound.

1 . A method of screening a chemical substance for possible solid forms, said method comprising the steps of: 
 preparing a first sample comprising a chemical substance in a first solvent;    preparing a second sample comprising the chemical substance in a second solvent;    sonicating the first and second samples; and    solidifying the chemical substance from the first and second samples.    
     
     
         2 . The method of  claim 1 , wherein the solidifying step and the sonicating step at least partially overlap.  
     
     
         3 . The method of  claim 1 , wherein at least one of said solvents is selected from the group consisting of acetone, acetonitrile, chloroform, dioxane, ethanol, ethyl acetate, heptane, butanone, methanol, nitromethane, tetrahydrofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane, methylcyclohexane, isopropyl alcohol, isopropyl acetate, trimethylpentane, n-octane, trichloroethane, trifluoroethanol, pyridine, propanol, butanol, tetrachloroethylene, chlorobenzene, xylene, dibutyl ether, methyl-tert-butyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, and dimethylformamide.  
     
     
         4 . The method of  claim 1 , wherein the first solvent comprises a mixture of solvents.  
     
     
         5 . The method of  claim 4 , wherein the second solvent comprises a mixture of solvents.  
     
     
         6 . The method of  claim 1 , wherein at least one of the samples is a solution having a viscosity greater than about 10 cPoise before the solution is sonicated.  
     
     
         7 . The method of  claim 1 , wherein the samples are provided by preparing a solution from an amorphous solid comprising the chemical substance.  
     
     
         8 . The method of  claim 7 , wherein the solvent is sonicated while the amorphous solid is added to the solvent.  
     
     
         9 . The method of  claim 1 , wherein at least one of the samples is an emulsion comprising two or more substantially immiscible solvents and the chemical substance.  
     
     
         10 . The method of  claim 1 , wherein at least one of the samples is a slurry comprising a solvent and the chemical substance.  
     
     
         11 . The method of  claim 1 , comprising providing a plurality of subsamples of said first sample, and wherein a first portion of the subsamples are subjected to relatively slow evaporation, and a second portion of the subsamples are subjected to relatively fast evaporation.  
     
     
         12 . The method of  claim 1 , wherein the solidifying step comprises evaporating a solvent from the samples, and the method comprises sonicating at least one of the samples until the solvent is substantially completely evaporated.  
     
     
         13 . The method of  claim 1 , comprising the step of evaporating a solvent from at least one of the samples during the sonicating step.  
     
     
         14 . The method of  claim 1 , comprising the step of evaporating a solvent from at least one of the samples after the sonicating step.  
     
     
         15 . The method of  claim 1 , comprising the step of cooling at least one of the samples before the sonicating step.  
     
     
         16 . The method of  claim 1 , comprising the step of cooling at least one of the samples during the sonicating step.  
     
     
         17 . The method of  claim 1 , comprising the step of cooling at least one of the samples after the sonicating step.  
     
     
         18 . The method of  claim 1 , comprising the step of crash-cooling at least one of the samples before the sonicating step.  
     
     
         19 . The method of  claim 1 , wherein at least one of the samples is sonicated by at least one ultrasound pulse.  
     
     
         20 . The method of  claim 1 , wherein at least one of the samples is sonicated by a series of at least 5 ultrasound pulses.  
     
     
         21 . The method of  claim 1 , wherein at least one of the samples is sonicated by sonicating at least once for about 5 minutes.  
     
     
         22 . The method of  claim 1 , wherein the sonication is substantially continuous during the solidification step.  
     
     
         23 . The method of  claim 1 , wherein the solidification comprises generating at least one solid solvate of the chemical substance.  
     
     
         24 . The method of  claim 1 , wherein the solidification comprises generating at least one solid hydrate of the chemical substance.  
     
     
         25 . The method of  claim 1 , wherein the first sample and the second sample are placed in a well plate.  
     
     
         26 . The method of  claim 25 , wherein the solidified chemical substances are analyzed in the well plate by x-ray diffraction.  
     
     
         27 . The method of  claim 1 , wherein the solidified chemical substances are analyzed by transmission x-ray diffraction.  
     
     
         28 . The method of  claim 1 , wherein the solidified chemical substances are analyzed by Raman spectroscopy.  
     
     
         29 . The method of  claim 1 , wherein the first sample and the second sample are sonicated in a well plate.  
     
     
         30 . The method of  claim 1 , further comprising the step of determining whether one or more solid forms were generated using an analytical method selected from the group consisting of visual analysis, microscopic analysis, thermal analysis, diffraction analysis, and spectroscopic analysis.  
     
     
         31 . The method of  claim 1 , further comprising the step of determining whether one or more solid forms were generated using x-ray diffraction analysis  
     
     
         32 . The method of  claim 1 , further comprising the step of determining whether one or more solid forms were generated using Raman spectroscopic analysis.  
     
     
         33 . A method of crystallizing a chemical substance, said method comprising the steps of: 
 forming an emulsion comprising two or more substantially immiscible solvents and the chemical substance by applying ultrasound to a mixture of said solvents and the chemical substance; and    crystallizing the chemical substance from the emulsion.    
     
     
         34 . The method of  claim 33 , further comprising the steps of adding an antisolvent to the emulsion, and thereafter further sonicating the emulsion.  
     
     
         35 . The method of  claim 33 , wherein the chemical substance is substantially soluble in one of said immiscible solvents and substantially insoluble in another of said immiscible solvents.  
     
     
         36 . A method of crystallizing a chemical substance, said method comprising the steps of: 
 providing a sample of the chemical substance in a solvent;    sonicating the sample at a predetermined supersaturation level; and    crystallizing the chemical substance from the sample.    
     
     
         37 . The method of  claim 36 , wherein the sonicating and crystallizing steps at least partially overlap.  
     
     
         38 . The method of  claim 36 , wherein the sample is cooled before sonicating.  
     
     
         39 . The method of  claim 36 , wherein the solvent is evaporated after sonicating.  
     
     
         40 . The method of  claim 36 , wherein the predetermined supersaturation level is selected to generate a relatively stable form of the chemical substance.  
     
     
         41 . The method of  claim 36 , wherein the predetermined supersaturation level is selected to generate a solvate of the chemical substance.  
     
     
         42 . The method of  claim 36 , further comprising adding an additional solvent to the sample.  
     
     
         43 . The method of  claim 36 , wherein the sample is a solution having a viscosity greater than about 10 cPoise before the solution is sonicated.  
     
     
         44 . The method of  claim 36 , wherein the sample has a metastable zone, and the metastable zone has a width of at least about 1° C.  
     
     
         45 . The method of  claim 36 , wherein the sample has a metastable zone, and the metastable zone has a width that is reduced by at least about 1° C. through sonicating the sample.  
     
     
         46 . The method of  claim 36 , wherein the forming step comprises forming a solution or suspension from a solvent and an amorphous solid comprising the chemical substance.  
     
     
         47 . A method of screening a chemical substance for possible solid forms, said method comprising the steps of: 
 providing a chemical substance in a plurality of samples;    sonicating at least one of the samples, wherein at least one other sample is unsonicated;    solidifying the samples of the chemical substance; and    determining whether one or more solid forms of the chemical substance were generated.    
     
     
         48 . A method of generating the most stable form of a chemical substance, said method comprising the steps of: 
 providing a sample of the chemical substance in a solvent;    sonicating the sample at a predetermined supersaturation level; and    crystallizing the chemical substance from the sample;    wherein the crystallized chemical substance is the most stable solid form of the chemical substance relative to known solid forms of the chemical substance.    
     
     
         49 . A method of generating a solid form of a chemical substance from a meta stable solution, said method comprising the steps of: 
 forming a metastable solution of the chemical substance in a solvent;    sonicating the metastable solution; and    crystallizing the chemical substance from the solution.    
     
     
         50 . A method of obtaining a substantially pure solid form of a chemical substance, said method comprising the steps of: 
 providing a sample of the chemical substance in a solvent;    sonicating the sample at a predetermined supersaturation level; and    crystallizing the chemical substance from the sample;    wherein a substantially pure solid form of the chemical substance is crystallized.    
     
     
         51 . A method of preparing a solvate of a chemical substance, said method comprising the steps of: 
 providing a sample comprising the chemical substance and a solvent;    sonicating the sample; and    generating a solid from the sample, wherein the solid comprises a solvate of the chemical substance and the solvent.    
     
     
         52 . A method of screening for possible cocrystals comprising an active agent, said method comprising the steps of: 
 providing a plurality of samples, each sample comprising the active agent and one or more guests, wherein the plurality of samples contains the same or different guests;    sonicating the samples;    crystallizing the active agent and the guest from the samples; and    determining whether a cocrystal was generated in one or more of the samples.    
     
     
         53 . The screening method of  claim 52 , wherein at least one sample contains a different guest than at least one other sample.  
     
     
         54 . The screening method of  claim 52 , wherein each sample contains a different guest.  
     
     
         55 . The screening method of  claim 52 , wherein the sonicating step and the crystallizing step at least partially overlap.  
     
     
         56 . The screening method of  claim 52 , wherein the samples are placed in a well plate and sonicated in the well plate.  
     
     
         57 . The screening method of  claim 52 , wherein the samples are supersaturated with respect to at least one of the active agent and the guest before the sonicating step.  
     
     
         58 . The method of  claim 52 , wherein at least some of the samples comprise more than one solvent.  
     
     
         59 . The method of  claim 52 , wherein the samples are sonicated by at least one ultrasound pulse.  
     
     
         60 . The method of  claim 52 , wherein at least one of the samples is sonicated by a series of ultrasound pulses, each pulse having a duration of from about 0.1 second to about 10 seconds.  
     
     
         61 . The method of  claim 52 , wherein at least one of the samples is sonicated at least once for at least about 1 minute.  
     
     
         62 . The method of  claim 52 , wherein at least one of the samples is sonicated at least once for at least about 5 minutes.  
     
     
         63 . The method of  claim 52 , further comprising the step of determining whether a cocrystal was generated using an analytical method selected from the group consisting of visual analysis, microscopic analysis, thermal analysis, diffraction analysis, and spectroscopic analysis.  
     
     
         64 . The method of  claim 52 , further comprising the step of determining whether a cocrystal was generated using x-ray diffraction analysis.  
     
     
         65 . The method of  claim 52 , further comprising the step of determining whether a cocrystal was generated using Raman spectroscopic analysis.  
     
     
         66 . The method of  claim 52 , wherein at Least one new solid state phase is formed by the crystallizing step.  
     
     
         67 . The method of  claim 52 , further comprising crystallizing at least one unsonicated sample that is substantially the same as at least one sonicated sample.  
     
     
         68 . A method of preparing a cocrystal comprising an active agent and a guest, said method comprising the steps of: 
 providing a sample of an active agent and a guest;    sonicating the sample; and    crystallizing a cocrystal from the sample, the cocrystal comprising the active agent and the guest.    
     
     
         69 . The method of  claim 68  wherein the active agent is an active pharmaceutical ingredient.  
     
     
         70 . The method of  claim 68 , wherein the active agent is provided as a salt in the sample.  
     
     
         71 . The method of  claim 70 , wherein the salt comprises chloride.  
     
     
         72 . The method of  claim 68 , wherein the guest is a salt.  
     
     
         73 . The method of  claim 68 , wherein the guest is an organic acid.  
     
     
         74 . The method of  claim 68 , wherein the active agent is not a salt.  
     
     
         75 . The method of  claim 68 , wherein the active agent is neutral or zwitterionic.  
     
     
         76 . The method of  claim 68 , wherein the sample comprises a solvent selected from the group consisting of acetone, acetonitrile, chloroform, 1,4-dioxane, ethanol, ethyl acetate, heptane, 2-butanone, methanol, nitromethane, tetrahydrofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane, methylcyclohexane, isopropyl alcohol, trimethylpentane, n-octane, trichloroethane, trifluoroethanol, pyridine, 1-butanol, tetrachloroethylene, chlorobenzene, xylene, dibutyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, and dimethylformamide.  
     
     
         77 . The method of  claim 68 , wherein the sample comprises more than one solvent.  
     
     
         78 . The method of  claim 68 , wherein the sample comprises more than one guest.  
     
     
         79 . The method of  claim 68 , wherein at least one of the samples is sonicated by at least one ultrasound pulse.  
     
     
         80 . The method of  claim 68 , wherein at least one of the samples is sonicated by a series of ultrasound pulses, each pulse having a duration of from about 0.1 second to about 10 seconds.  
     
     
         81 . The method of  claim 68 , wherein at least one of the samples is sonicated at least once for at least about 1 minute.  
     
     
         82 . The method of  claim 68 , wherein at least one of the samples is sonicated at least once for at least about 5 minutes.  
     
     
         83 . The method of  claim 68 , wherein the sonication is substantially continuous during the crystallization step.  
     
     
         84 . A method of cocrystallizing two or more components, said method comprising the steps of: 
 (a) determining a concentration for two or more components in a sample effective for cocrystallization of the components;    (b) preparing the sample comprising the components, said sample having an effective concentration of the components;    (c) sonicating the sample; and    (d) generating a cocrystal from the sample, the cocrystal comprising the components.    
     
     
         85 . The method of  claim 84 , wherein the components comprise an active agent and a guest.  
     
     
         86 . A method for speeding the cocrystallization of an active agent and a guest comprising: 
 providing a sample in an effective volume;    sonicating the sample;    cocrystallizing said active agent and said guest from the sample;    wherein the rate of cocrystallization is increased by at least 25%.    
     
     
         87 . The method of  claim 84 , wherein the sample is a metastable solution.  
     
     
         88 . A method for screening for possible salts comprising an ionizable active agent, said method comprises: 
 providing a plurality of samples comprising an ionizable active agent and one or more counterions, wherein the plurality of samples contains the same or different counterions;    sonicating the samples;    forming one or more crystallized salt compounds from the samples, said crystallized salt compounds comprising the ionizable active agent and the counterions.    
     
     
         89 . The method of  claim 88 , wherein at least one sample contains a different counterion than at least one other sample.  
     
     
         90 . The method of  claim 88 , wherein the plurality of samples comprises a plurality of sets, and the sets differ in having different counterions, and the samples within each set have the same counterion.