Submicron suspensions with polymorph control

Abstract

The present invention provides a method for preparing a suspension of a pharmaceutically active compound, the solubility of which is greater in a water miscible first organic solvent than in a second solvent which is aqueous, The process includes the steps of: (i) dissolving a first quantity of the pharmaceutically active compound in the water miscible first organic solvent to form a first solution; (ii) mixing the first solution with the second solvent to precipitate the pharmaceutically active compound; and (iii) seeding the first solution or the second solvent or the presuspension.

1 . A method for preparing a suspension of a pharmaceutically-active compound, the solubility of which is greater in a water miscible first organic solvent than in a second solvent which is aqueous, the process comprising the steps of: 
 (i) dissolving a first quantity of the pharmaceutically-active compound in the water-miscible first organic solvent to form a first solution;    (ii) mixing the first solution with the second solvent to precipitate the pharmaceutically-active compound to create a presuspension; and    (iii) seeding the first solution or the second solvent prior to the or the presuspension after the mixing step.    
   
   
       2 . The method of  claim 1  wherein the step of precipitating the pharmaceutically-active compound comprises the step of precipitating the compound in a form selected from the group consisting of a supercooled liquid, an amorphous particle, a semicrystalline particle and a crystalline particle.  
   
   
       3 . The method of  claim 2  further comprising the step of adding energy to the presuspension.  
   
   
       4 . The method of  claim 3  wherein the adding-energy step comprises the step of subjecting the presuspension to high energy agitation.  
   
   
       5 . The method of  claim 3  wherein the adding energy step comprises the step of adding heat to the presuspension.  
   
   
       6 . The method of  claim 3  wherein the energy addition step comprises the step of exposing the presuspension to electromagnetic energy.  
   
   
       7 . The method of  claim 6  wherein the step of exposing the presuspension to electromagnetic energy comprises the step of exposing the presuspension to a laser beam.  
   
   
       8 . The method of  claim 1  further comprising the step of forming a desired polymorph of the pharmaceutically active compound.  
   
   
       9 . The method of  claim 8  wherein the step of seeding comprises the step of using a seed compound.  
   
   
       10 . The method of  claim 9  wherein the seed compound is the desired polymorph of the pharmaceutically-active compound.  
   
   
       11 . The method of  claim 9  wherein the seed compound is a compound other than the desired polymorph of the pharmaceutically-active compound.  
   
   
       12 . The method of  claim 11  wherein the seed compound is selected from the group consisting of: an inert impurity; and an organic compound with a structure similar to that of the desired polymorph.  
   
   
       13 . The method of  claim 9  wherein the seed compound is added to the first solution.  
   
   
       14 . The method of  claim 9  wherein the seed compound is added to the second solvent.  
   
   
       15 . The method of  claim 9  wherein the seed compound is added to the presuspension.  
   
   
       16 . The method of  claim 8  wherein the step of forming a desired polymorph comprises the step of forming a seed compound in the first solution.  
   
   
       17 . The method of  claim 16  wherein the step of forming the seed compound in the first solution comprises the step of adding the pharmaceutically-active compound in sufficient quantity to exceed the solubility of the pharmaceutically-active compound in the first solvent to create a supersaturated solution.  
   
   
       18 . The method of  claim 17  wherein the step of forming the seed compound in the first solution further comprises the step of treating the supersaturated solution.  
   
   
       19 . The method of  claim 18  wherein the step of treating the supersaturated solution comprises the step of aging the supersaturated solution.  
   
   
       20 . The method of  claim 1  wherein the seeding step comprises the step of using electromagnetic energy.  
   
   
       21 . The method of  claim 20  wherein the electromagnetic energy is dynamic electromagnetic energy.  
   
   
       22 . The method of  claim 20  wherein the electromagnetic energy is a laser beam.  
   
   
       23 . The method of  claim 20  wherein the electromagnetic energy is radiation.  
   
   
       24 . The method of  claim 1  wherein the step of seeding comprises the step of using a particle beam.  
   
   
       25 . The method of  claim 1  wherein the step of seeding comprises the step of using an electron beam.  
   
   
       26 . The method of  claim 1  wherein the step of seeding comprises using ultrasound.  
   
   
       27 . The method of  claim 1  wherein the step of seeding comprises using a static electrical field.  
   
   
       28 . The method of  claim 1  wherein the step of seeding comprises using a static magnetic field.  
   
   
       29 . The method of  claim 1  further comprising the steps of forming particles having an average effective particle size less than about 2 μm.  
   
   
       30 . A method for preparing a suspension of a pharmaceutically-active compound, the solubility of which is greater in a water-miscible first organic solvent than in a second solvent which is aqueous, the process comprising the steps of: 
 (i) dissolving a first quantity of the pharmaceutically-active compound in the water-miscible first organic solvent to form a first solution;    (ii) mixing the first solution with the second solvent to precipitate the pharmaceutically active compound to create a presuspension; and    (iii) providing a seed compound to the first solution or the second solvent or the presuspension.    
   
   
       31 . The method of  claim 30  further comprising the step of adding energy to the presuspension to provide particles having an average effective particle size of less than about 2 μm.  
   
   
       32 . The method of  claim 30  further comprising the step of forming a desired polymorph of the pharmaceutically active compound.  
   
   
       33 . The method of  claim 32  wherein the step of seeding comprises the step of providing a seed compound.  
   
   
       34 . The method of  claim 33  wherein the seed compound is the desired polymorph of the pharmaceutically-active compound.  
   
   
       35 . The method of  claim 33  wherein the seed compound is a compound other than the desired polymorph of the pharmaceutically-active compound.  
   
   
       36 . The method of  claim 35  wherein the seed compound is selected from the group consisting of: an inert impurity; and an organic compound with a structure similar to that of the desired polymorph.  
   
   
       37 . The method of  claim 33  wherein the seed compound is added to the first solution.  
   
   
       38 . The method of  claim 33  wherein the seed compound is added to the second solvent.  
   
   
       39 . The method of  claim 33  wherein the seed compound is added to the presuspension.  
   
   
       40 . The method of  claim 32  wherein the step of forming a desired polymorph comprises the step of forming a seed compound in the first solution.  
   
   
       41 . The method of  claim 40  wherein the step of forming the seed compound in the first solution comprises the step of adding the pharmaceutically-active compound in sufficient quantity to exceed the solubility of the pharmaceutically-active compound in the first solvent to create a supersaturated solution.  
   
   
       42 . The method of  claim 41  wherein the step of forming the seed compound in the first solution further comprises the step of treating the supersaturated solution.  
   
   
       43 . The method of  claim 41  wherein the step of treating the supersaturated solution comprises the step of aging the supersaturated solution.  
   
   
       44 . A method for preparing a suspension of a pharmaceutically-active compound, the solubility of which is greater in a water-miscible first organic solvent than in a second solvent which is aqueous, the process comprising the steps of: 
 (i) adding a quantity of the pharmaceutically-active compound to the first organic solvent to create a supersaturated solution;    (ii) aging the supersaturated solution to form detectable crystals to create a seeding mixture; and    (iii) mixing the seeding mixture with the second solvent to precipitate the pharmaceutically-active compound to create a presuspension.    
   
   
       45 . The method of  claim 44  wherein the pharmaceutically-active compound of the presuspension is in a form selected from the group consisting of a supercooled liquid, an amorphous particle, a semicrystalline particle and a crystalline particle.  
   
   
       46 . The method of  claim 45  further comprising the step of converting the compound in the presuspension to a desired polymorph.  
   
   
       47 . The method of  claim 46  wherein the step of converting the compound of the presuspension comprises the step of adding energy to the presuspension.  
   
   
       48 . The method of  claim 47  wherein the adding-energy step comprises the step of subjecting the presuspension to high energy agitation.  
   
   
       49 . The method of  claim 47  wherein the adding-energy step comprises the step of adding heat to the presuspension.  
   
   
       50 . The method of  claim 47  wherein the adding-energy step comprises the step of exposing the presuspension to electromagnetic energy.  
   
   
       51 . The method of  claim 47  wherein the step of exposing the presuspension to electromagnetic energy comprises the step of exposing the presuspension to a laser beam.  
   
   
       52 . The method of  claim 44  further comprising the steps of: adding energy to the pre-suspension to form particles having an average effective particle size of less than about 2 μm.  
   
   
       53 . A method for preparing a suspension of a pharmaceutically-active compound, the solubility of which is greater in a water-miscible first organic solvent than in a second solvent which is aqueous, the process comprising the steps of: 
 (i) adding a quantity of the pharmaceutically-active compound to the first organic solvent to create a supersaturated solution;    (ii) treating the supersaturated solution to form a detectable crystal to create a seeding mixture; and    (iii) mixing the seeding mixture with the second solvent to precipitate the pharmaceutically-active compound.    
   
   
       54 . The method of  claim 53 , wherein the treating step comprises aging.  
   
   
       55 . The method of  claim 53 , wherein the treating step comprises adding a surfactant.  
   
   
       56 . The method of  claim 53 , wherein the treating step comprises adding a crystallization modifier.  
   
   
       57 . The method of  claim 53 , wherein the treating step comprises dropping the temperature.  
   
   
       58 . The method of  claim 53 , wherein the treating step comprises using a laser beam.  
   
   
       59 . The method of  claim 53 , wherein the treating step comprises using radiation.  
   
   
       60 . The method of  claim 53 , wherein the treating step comprises using a particle beam.  
   
   
       61 . The method of  claim 53 , wherein the treating step comprises using an electron beam.  
   
   
       62 . The method of  claim 53  wherein the treating step comprises using ultrasound.  
   
   
       63 . The method of  claim 53  wherein the treating step comprises using a static electrical field.  
   
   
       64 . The method of  claim 53 , wherein the treating step comprises using a static magnetic field.  
   
   
       65 . A composition of matter of a polymorphic pharmaceutically-active compound in a desired polymorphic form essentially free of an unspecified polymorphic form.  
   
   
       66 . The composition of  claim 65  wherein the pharmaceutically-active compound is itraconazole.