Method for preparing submicron particle suspensions

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 pre-suspension.

1 - 97 . (canceled)  
     
     
         98 . 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 pre-suspension; and (iii) seeding the first solution or the second solvent prior to the or the mixing step pre-suspension after the mixing step.  
     
     
         99 . The method of  claim 98  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.  
     
     
         100 . The method of  claim 99  further comprising the step of adding energy to the pre-suspension.  
     
     
         101 . The method of  claim 100  wherein the adding-energy step comprises the step of subjecting the pre-suspension to high energy agitation.  
     
     
         102 . The method of  claim 100  wherein the adding-energy step comprises the step of adding heat to the pre-suspension.  
     
     
         103 . The method of  claim 100  wherein the energy-addition step comprises the step of exposing the pre-suspension to electromagnetic energy.  
     
     
         104 . The method of  claim 103  wherein the step of exposing the pre-suspension to electromagnetic energy comprises the step of exposing the pre-suspension to a laser beam.  
     
     
         105 . The method of  claim 98  further comprising the step of forming a desired polymorph of the pharmaceutically active compound.  
     
     
         106 . The method of  claim 105  wherein the step of seeding comprises the step of using a seed compound.  
     
     
         107 . The method of  claim 105  wherein the seed compound is the desired polymorph of the pharmaceutically-active compound.  
     
     
         108 . The method of  claim 105  wherein the seed compound is a compound other than the desired polymorph of the pharmaceutically-active compound.  
     
     
         109 . The method of  claim 108  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.  
     
     
         110 . The method of  claim 105  wherein the seed compound is added to the first solution.  
     
     
         111 . The method of  claim 105  wherein the seed compound is added to the second solvent.  
     
     
         112 . The method of  claim 105  wherein the seed compound is added to the pre-suspension.  
     
     
         113 . The method of  claim 104  wherein the step of forming a desired polymorph comprises the step of forming a seed compound in the first solution.  
     
     
         114 . The method of  claim 113  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.  
     
     
         115 . The method of  claim 114  wherein the step of forming the seed compound in the first solution further comprises the step of treating the supersaturated solution.  
     
     
         116 . The method of  claim 115  wherein the step of treating the supersaturated solution comprises the step of aging the supersaturated solution.  
     
     
         117 . The method of  claim 116  wherein the seeding step comprises the step of using electromagnetic energy.  
     
     
         118 . The method of  claim 117  wherein the electromagnetic energy is dynamic electromagnetic energy.  
     
     
         119 . The method of  claim 117  wherein the electromagnetic energy is a laser beam.  
     
     
         120 . The method of  claim 117  wherein the electromagnetic energy is radiation.  
     
     
         121 . The method of  claim 98  wherein the step of seeding comprises the step of using a particle beam.  
     
     
         122 . The method of  claim 98  wherein the step of seeding comprises the step of using an electron beam.  
     
     
         123 . The method of  claim 98  wherein the step of seeding comprises using ultrasound.  
     
     
         124 . The method of  claim 98  wherein the step of seeding comprises using a static electrical field.  
     
     
         125 . The method of  claim 98  wherein the step of seeding comprises using a static magnetic field.  
     
     
         126 . The method of  claim 98  further comprising the steps of forming particles having an average effective particle size less than about 2 μm.  
     
     
         127 . A composition of matter of a polymorphic pharmaceutically-active compound in a desired polymorphic form essentially free of an unspecified polymorphic form.  
     
     
         128 . The composition of  claim 127  wherein the pharmaceutically-active compound is itraconazole.