Method and apparatus for the formation of particles

Abstract

The invention provides a method for forming particles of a substance, by co-introducing into a particle formation vessel, in which the temperature and pressure are controlled, of a supercritical fluid; a solution or suspension of the substance in a first vehicle; and a second vehicle which is both substantially miscible with the first vehicle and substantially soluble in the supercritical fluid, in such a way that dispersion of the solution or suspension and the second vehicle, and extraction of the vehicles, occur substantially simultaneously and substantially immediately on introduction of the fluids into the vessel, by the action of the supercritical fluid. Preferably the solution/suspension of the substance is introduced separately from the second vehicle, in such a way that contact between the solution/suspension and the second vehicle occurs either substantially simultaneously with, or immediately before, their dispersion by the supercritical fluid and extraction of the vehicles by the supercritical fluid. The method allows a high degree of control over the size, shape, crystalline form and other physico-chemical properties of the particulate product. The invention also provides apparatus for carrying out such a method, using a coaxial nozzle to introduce the fluids into the particle formation vessel, and a particulate product made using the method or the apparatus.

1 . A method for forming particles of a substance, the method comprising the co-introduction into a particle formation vessel, the temperature and pressure in which are controlled, of a super-critical fluid; a solution or suspension of the substance in a first vehicle; and a second vehicle which is both substantially miscible with the first vehicle and substantially soluble in the supercritical fluid, in such a way that dispersion of the solution or suspension and the second vehicle, and extraction of the vehicles, occur substantially simultaneously and substantially immediately on introduction of the fluids into the particle formation vessel, by the action of the supercritical fluid.  
     
     
         2 . A method according to  claim 1 , wherein the solution or suspension of the substance in the first vehicle is introduced into the particle formation vessel separately from the second vehicle, in such a way that contact between the solution or suspension and the second vehicle occurs either substantially simultaneously with, or immediately before, dispersion of the solution or suspension and the second vehicle by the action of the supercritical fluid and extraction of the vehicles by the supercritical fluid.  
     
     
         3 . A method according to  claim 1  or  claim 2 , wherein the substance is soluble, or substantially soluble, only in solvents which are themselves substantially insoluble in the supercritical fluid or is incompatible with a solvent which is soluble or substantially soluble in the supercritical fluid.  
     
     
         4 . A method according to  claim 2  or  claim 3 , wherein an excess of the second vehicle over the first is achieved at their moment of contact, by means of appropriate flow rates for the two vehicles on their introduction into the particle formation vessel.  
     
     
         5 . A method according to any one of the preceding claims, wherein the amount of the first vehicle used is less than or equal to about 30% of the total amount of the first and second vehicles used.  
     
     
         6 . A method according to any one of the preceding claims, wherein the supercritical fluid contains one or more modifiers.  
     
     
         7 . A method according to any one of the preceding claims, wherein one of the two vehicles contains functional groups that can hydrogen-bond or otherwise interact with functional groups contained in the other vehicle.  
     
     
         8 . A method according to any one of the preceding claims, wherein the substance and the first vehicle are substantially polar, the second vehicle is substantially non-polar and both vehicles are substantially miscible in all proportions and substantially soluble in the supercritical fluid.  
     
     
         9 . A method according to any one of claims  1 - 7 , wherein the substance and the first vehicle are substantially non-polar, the second vehicle is substantially polar and both vehicles are substantially miscible in all proportions and substantially soluble in the supercritical fluid.  
     
     
         10 . A method according to any one of the preceding claims wherein the substance is substantially insoluble in the second vehicle.  
     
     
         11 . A method according to  claim 10 , wherein the second vehicle contains a crystallisation seed, of an appropriate material which is insoluble in the second vehicle, to induce nucleation of the substance from which particles are to be formed, when the second vehicle comes into contact with the solution or suspension of the substance in the first vehicle.  
     
     
         12 . A method according to  claim 11 , wherein the substance from which particles are to be formed is for use in or as a pharmaceutical, and the seed is or comprises a pharmaceutically acceptable carrier for the substance.  
     
     
         13 . A method according to any one of the preceding claims, wherein the supercritical fluid, the solution or suspension and the second vehicle are co-introduced into the particle formation vessel by means of 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 to one another at the outlet end, at least one of the passages serving to introduce a flow of the supercritical fluid into the particle formation vessel, at least one of the passages serving to introduce a flow of the solution or suspension of the substance in the first vehicle and at least one of the passages serving to introduce a flow of the second vehicle.  
     
     
         14 . A method according to  claim 13 , wherein the nozzle is able to cause pre-filling of the solution or suspension and/or the second vehicle to occur, immediately prior to their dispersion by the supercritical fluid.  
     
     
         15 . A method according to  claim 13  or  claim 14 , wherein the solution or suspension of the substance in the first vehicle is introduced into the particle formation vessel through one passage of toe nozzle, and the supercritical fluid and the second vehicle are introduced together through another passage of the nozzle, such that mixing of the two vehicles can occur simultaneously with their dispersion and extraction by the supercritical fluid.  
     
     
         16 . A method according to  claim 15 , wherein the nozzle has at least three coaxial passages, the solution or suspension being introduced between an inner and an outer flow of the supercritical fluid/second vehicle mixture.  
     
     
         17 . A method according to  claim 13  or  claim 14 , wherein the nozzle has at least three coaxial passages, the outlet of at least one of the inner nozzle passages being located a small distance upstream (in use) of the outlet of one of its surrounding passages, and wherein the solution or suspension and the second vehicle are introduced through the inner passage and surrounding passage in question so as to allow, in use, a degree of mixing to occur, between the solution or suspension and the second vehicle, within the nozzle.  
     
     
         18 . A method according to  claim 17 , wherein the nozzle has at least four coaxial passages, and wherein the solution or suspension and the second vehicle are introduced into the particle formation vessel between an inner and an outer flow of the supercritical fluid.  
     
     
         19 . A method according to any one of the preceding claims, wherein one or more of the following conditions is varied in order to control the size and/or size distribution and/or shape and/or crystalline form of the particles formed: the flow rate(s) of the supercritical fluid and/or the solution or suspension and/or the second vehicle; the relative amounts of the two vehicles; the concentration of the substance in the first vehicle; the temperature inside the particle formation vessel; and the pressure inside the particle formation vessel.  
     
     
         20 . A method according to any one of the preceding claims, wherein the pressure inside the particle formation vessel is maintained substantially in excess of the critical pressure of the fluid used as the supercritical fluid, whilst the temperature inside the particle formation vessel is maintained at only slightly above the critical temperature for that fluid.  
     
     
         21 . A method according to any one of the preceding claims, wherein the ratio of the solution/suspension flow rate, into the particle formation vessel, to that of the supercritical fluid is between 0.001 and 0.2.  
     
     
         22 . A method according to any one of the preceding claims, which is carried out substantially continuously, as opposed to batch-wise.  
     
     
         23 . A method for forming particles of a substance, the method being substantially as herein described with reference to the accompanying illustrative drawings.  
     
     
         24 . Apparatus for use in carrying out a method according to any one of the preceding claims, the apparatus comprising a particle formation vessel; means for controlling the temperature in the vessel at a desired level; means for controlling the pressure in the vessel at a desired level; and means for the co-introduction, into the vessel, of the supercritical fluid, the solution or suspension of the substance in the first vehicle, and the second vehicle, in such a way that contact between the solution or suspension and the second vehicle occurs either substantially simultaneously with, or immediately before, dispersion of the solution or suspension and the second vehicle by the action of the supercritical fluid and extraction of the vehicles by the supercritical fluid, and such that the dispersion and extraction occur substantially simultaneously and substantially immediately on introduction of the fluids into the particle formation vessel, wherein the mean; for the co-introduction of the fluids into the vessel comprises a nozzle having an outlet end communicating with the interior of the vessel, and at least three coaxial passages which terminate adjacent or substantially adjacent to one another at the outlet end, at least one of the passages serving to introduce a flow of the supercritical fluid into the vessel, at least one of the passages serving to introduce a flow of the solution or suspension and at least one of the passages serving to introduce a flow of the second vehicle, all fluid flows being in substantially coaxial directions, and wherein the outlet of at least one of the inner nozzle passages is located a small distance upstream (in use) of the outlet of one of its surrounding passages so as to allow, in use, a degree of mixing to occur within the nozzle, between the solution or suspension and the second vehicle, when the solution/suspension and the second vehicle are introduced through the inner passage and surrounding passage in question.  
     
     
         25 . Apparatus according to  claim 24 , wherein the nozzle is able to cause pre-filming of the solution or suspension and/or the second vehicle to occur, immediately prior to their dispersion by the supercritical fluid.  
     
     
         26 . Apparatus according to  claim 24  or  claim 25 , wherein the nozzle has four coaxial passages.  
     
     
         27 . Apparatus according to any one of claims  24 - 26 , wherein the angle of taper of the outlet end of the nozzle, with respect to the main axis of the nozzle, is in the range of about 10° to about 60°.  
     
     
         28 . Apparatus according to any one of claims  24 - 27 , comprising more than one particle formation vessel and/or more than one means for collecting the particles formed, thereby allowing for the substantially continuous operation of the apparatus through switching from one particle formation vessel or collection means to another as required.  
     
     
         29 . Apparatus according to any one of claims  24 - 28  and substantially as herein described with reference to the accompanying illustrative drawings.  
     
     
         30 . A particulate product made using a method according to any one of claims  1 - 23 , and/or apparatus according to any one of claims  24 - 29 .