Methods and apparatus for particle formation

Abstract

The invention provides a method for forming particles of a target substance ( 26 ), involving: (a) preparing a solution or suspension of the substance in a vehicle ( 21 ) which is or includes either a near-critical fluid ( 21 ) or a first supercritical fluid; (b) introducing the solution or suspension into a particle formation vessel ( 32 ); and (c) contacting the solution or suspension, in the particle formation vessel, with a second supercritical fluid, under conditions which allow the second supercritical fluid to cause precipitation of particles of the target substance from the solution or suspension; wherein the second supercritical fluid is miscible or substantially miscible with the vehicle and is a fluid in which the target substance is insoluble or substantially insoluble. Also provided is apparatus for use in carrying out an embodiment of the method, including a particle formation vessel and means for controlling the temperature and pressure inside it; a fluid mixing vessel and means for controlling the temperature and pressure inside it; first fluid inlet means for introducing into the fluid mixing vessel a vehicle and a solution of a target substance in a primary solvent, so as to form in the fluid mixing vessel a solution of the substance and the primary solvent in the vehicle; and second fluid inlet means for introducing the solution thus formed, preferably together with a second supercritical fluid, into the particle formation vessel. The invention also provides a particulate product formed using the method.

1 . A method for forming particles of a target substance, the method involving: 
 (a) preparing a solution or suspension of the target substance in a vehicle which is or includes either a near-critical fluid or a first supercritical fluid;    (b) introducing the solution or suspension into a particle formation vessel; and    (c) contacting the solution or suspension, in the particle formation vessel, with a second supercritical fluid, under conditions which allow the second supercritical fluid to cause precipitation of particles of the target substance from the solution or suspension; 
 wherein the second supercritical fluid is miscible or substantially miscible with the vehicle and is a fluid in which the target substance is insoluble or substantially insoluble.  
   
     
     
         2 . A method according to  claim 1 , wherein the solution or suspension and the second supercritical fluid are co-introduced into the particle formation vessel through a fluid inlet means which allows the second supercritical fluid to disperse the solution or suspension, at the same time as it causes precipitation from it.  
     
     
         3 . A method according to  claim 2 , wherein the solution or suspension and the second supercritical fluid are co-introduced into the particle formation vessel through a fluid inlet means which allows them both to enter the vessel at the same or substantially the same point, which is also the as, or substantially the same as, the point where they meet and at which the second supercritical fluid disperses the solution or suspension and causes particle precipitation.  
     
     
         4 . A method according to  claim 2  or  claim 3 , wherein the fluid inlet means is of the type which allows “pre-filming” or “sheathing” of the solution or suspension to occur, immediately prior to its dispersion by the second supercritical fluid.  
     
     
         5 . A method according to any one of  claims 2  to  4 , wherein the second supercritical fluid and the solution or suspension are co-introduced into the particle formation vessel with coaxial or substantially coaxial flows, using as the fluid inlet means a nozzle having an outlet end communicating with the interior of the particle formation vessel and two or more coaxial passages which terminate adjacent or substantially adjacent one another at the outlet end, at least one of the passages serving to introduce a flow of the second supercritical fluid, and at least one of the passages serving to introduce a flow of the solution or suspension.  
     
     
         6 . A method according to any one of the preceding claims, wherein the target substance is non-polar or of fairly low polarity, the vehicle is also of low polarity and the second supercritical fluid has a relatively high polarity.  
     
     
         7 . A method according to any one of the preceding claims, wherein the vehicle is a supercritical fluid.  
     
     
         8 . A method according to  claim 7 , wherein the vehicle is supercritical carbon dioxide.  
     
     
         9 . A method according to any one of the preceding claims, wherein the vehicle contains one or more modifiers.  
     
     
         10 . A method according to any one of the preceding claims, wherein the second supercritical fluid is supercritical nitrogen.  
     
     
         11 . A method according to any one of  claims 1  to  9 , wherein the second supercritical fluid is a supercritical noble gas.  
     
     
         12 . A method according to any one of the preceding claims, wherein the second supercritical fluid contains one or more modifiers.  
     
     
         13 . A method according to any one of the preceding claims, wherein the temperature of the second supercritical fluid is between 1.01 and 4 times its critical temperature (in Kelvin).  
     
     
         14 . A method according to any one of the preceding claims, wherein the flow rate of the second supercritical fluid into the particle formation vessel, measured at or immediately prior to its contact with the solution or suspension, is higher than that of the solution or suspension.  
     
     
         15 . A method according to  claim 14 , wherein the flow rate of the second supercritical fluid is between 10 and 20 times greater than that of the solution or suspension.  
     
     
         16 . A method according to any one of the preceding claims, wherein the flow rates of the second supercritical fluid and the solution or suspension are such that the vehicle constitutes between 1 and 20 mole % of the fluid mixture formed when the fluids come into contact with one another.  
     
     
         17 . A method according to any one of the preceding claims, additionally involving controlling the flow rate of one or more of the fluids to influence the characteristics of the particulate product.  
     
     
         18 . A method according to any one of the preceding claims, wherein back-flow of the second supercritical fluid, into the supply line for the solution or suspension, is reduced or eliminated by means of a one-way valve in the solution or suspension supply line, upstream of the point of contact between the second supercritical fluid and the solution/suspension, and/or by maintaining the supplied pressure of the solution or suspension, to the particle formation vessel, in excess of that of the second supercritical fluid.  
     
     
         19 . A method according to any one of the preceding claims, wherein the fluids are introduced into the particle formation vessel with a pulse-less or substantially pulse-less flow.  
     
     
         20 . A method according to any one of the preceding claims, wherein the target substance is highly soluble in the vehicle, the method involving dissolving the substance directly in the vehicle and introducing the resultant solution into the particle formation vessel to contact the second supercritical fluid.  
     
     
         21 . A method according to any one of  claims 1  to  19 , involving producing a solution of the target substance in a primary solvent in which it is more soluble than in the vehicle; dissolving the resultant solution in, or mixing it with, the vehicle or a sub-critical form thereof; and then contacting the resulting solution (in the form of a supercritical or near-critical fluid) with the second supercritical fluid in the particle formation vessel.  
     
     
         22 . A method according to  claim 21 , wherein the solution of the target substance in the primary solvent is dissolved in or mixed with the vehicle by dispersing the solution into a fluid mixing vessel together with the vehicle, using a fluid inlet means which allows both the solution and the vehicle to enter the vessel at the same or substantially the same point, which is also the same as, or substantially the same as, the point where they meet, and which allows the vehicle to disperse the solution at or substantially at the point where the fluids enter the fluid mixing vessel.  
     
     
         23 . A method according to any one of the preceding claims, wherein the target substance is for use in or as a pharmaceutical.  
     
     
         24 . A method for forming particles of a target substance, the method being substantially as herein described with reference to the accompanying illustrative drawings.  
     
     
         25 . Apparatus for use in carrying out a method according to  claim 21  or  claim 22 , the apparatus including a particle formation vessel; means for controlling the temperature and pressure in the particle formation vessel at desired levels; a fluid mixing vessel; means for controlling the temperature and pressure in the fluid mixing vessel at desired levels; first fluid inlet means for introducing into the fluid mixing vessel a vehicle and a solution of a target substance in a primary solvent, so as to form in the fluid mixing vessel a solution of the target substance and the primary solvent in the vehicle; and second fluid inlet means for introducing the solution thus formed, preferably together with a second supercritical fluid, into the particle formation vessel.  
     
     
         26 . Apparatus according to  claim 25 , wherein the first fluid inlet means allows both the solution of the target substance in the primary solvent, and the vehicle, to enter the fluid mixing vessel at the same or substantially the same point, which is also the same as, or substantially the same as, the point where they meet, and wherein the first fluid inlet means also allows the vehicle to disperse the solution at or substantially at the point where the fluids enter the fluid mixing vessel.  
     
     
         27 . Apparatus according to  claim 25  or  claim 26 , wherein the second fluid inlet means allows both the solution of the target substance and the primary solvent in the vehicle, and the second supercritical fluid, to enter the particle formation vessel at the same or substantially the same point, which is also the same as, or substantially the same as, the point where they meet, and which allows the second supercritical fluid to disperse the solution at or substantially at the point where the fluids enter the vessel.  
     
     
         28 . Apparatus for use in carrying out a method according to  claim 21  or  claim 22 , the apparatus being substantially as herein described with reference to the accompanying illustrative drawings.