Particle formation

Abstract

Method for preparing a target substance in particulate form, comprising introducing into a particle formation vessel, through separate first and second fluid inlets respectively, (a) a “target solution/suspension” of the substance in a fluid vehicle and (b) a compressed fluid anti-solvent, and allowing the anti-solvent to extract the vehicle so as to form particles of the substance, wherein the anti-solvent fluid has a sonic, near-sonic or supersonic velocity as it enters the vessel, and wherein the anti-solvent and the target solution/suspension enter the vessel at different locations and meet downstream (in the direction of anti-solvent flow) of the second fluid inlet. Also provided is apparatus for use in such a method.

1 . A method for preparing a pharmaceutical substance in particulate form, the method comprising: 
 separately introducing into a particle formation vessel the substance in a fluid vehicle through a first fluid inlet;    separately introducing into the particle formation vessel a compressed fluid anti-solvent for the substance through a second fluid inlet; and    allowing the compressed fluid anti-solvent to extract the fluid vehicle from the substance to form particles of the substance, wherein the compressed fluid anti-solvent has a sonic, near-sonic or supersonic velocity as it enters the particle formation vessel, and wherein the compressed fluid anti-solvent and the substance in the fluid vehicle enter the particle formation vessel at different locations and contact each other after their point of entry.    
     
     
         2 . The method of  claim 1 , wherein the substance in the fluid vehicle is a solution, a suspension or a combination thereof.  
     
     
         3 . The method of  claim 2 , wherein the compressed fluid anti-solvent is a supercritical or near-critical fluid.  
     
     
         4 . The method of  claim 3 , wherein the supercritical fluid or near-critical fluid contains a compound selected from the group consisting of carbon dioxide, nitrogen, nitrous oxide, sulfur hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane, trifluoromethane, helium, neon, derivatives thereof and combinations thereof.  
     
     
         5 . The method of  claim 1 , wherein: 
 the pressure in the particle formation vessel is P 1 ; and    the compressed fluid anti-solvent is introduced through a restricted inlet so as to have a back pressure of P 2  as it is introduced into the particle formation vessel, where P 2  is greater than P 1 .    
     
     
         6 . The method of  claim 5 , wherein: 
 the temperature in the particle formation vessel is T 1 ; and    the compressed fluid anti-solvent is introduced into the particle formation vessel at a temperature T 2 , where T 2  is greater than T 1 .    
     
     
         7 . The method of  claim 6 , wherein T 1  and T 2  are such that Joule-Thomson cooling of the compressed fluid anti-solvent as it enters the particle formation vessel does not reduce the temperature of the compressed fluid anti-solvent to below a critical temperature T c  of the anti-solvent.  
     
     
         8 . The method of  claim 7 , wherein P 1 , P 2 , T 1  and T 2  are such that the compressed fluid anti-solvent has a sonic, near-sonic or supersonic velocity as it enters the particle formation vessel.  
     
     
         9 . The method of  claim 8 , wherein: 
 the compressed fluid anti-solvent is supercritical or near-critical carbon dioxide;    P 1  is between about 75 bar and about 350 bar;    P 2  is between about 250 bar and about 350 bar;    T 1  is between about 31° C. and about 100° C.; and    T 2  is between about 80° C. and about 170° C.,    
     
     
         10 . The method of  claim 9 , wherein 
 the carbon dioxide has a flow rate of between about 170 g/min and about 200 g/min; and    P 1  and P 2  have a difference between about 170 bar and about 250 bar.    
     
     
         11 . The method of  claim 6 , wherein: 
 P 1  is greater than a critical pressure P c  of the anti-solvent,    T 1  is greater than a critical temperature T c  of the anti-solvent; and    T 1  and T 2  are such that the temperature of the compressed fluid anti-solvent does not fall below T c  within the particle formation vessel.    
     
     
         12 . The method of  claim 2 , wherein on entering the particle formation vessel, the compressed fluid anti-solvent has a Mach number between about 0.8 and about 1.5.  
     
     
         13 . The method of  claim 2 , wherein the near-sonic, sonic or supersonic velocity of the compressed fluid anti-solvent is achieved by introducing the compressed fluid anti-solvent into the particle formation vessel as a single stream through a convergent nozzle, without the aid of further mechanical, electrical and/or magnetic input.  
     
     
         14 . The method of  claim 2 , wherein a Mach disk is generated in the compressed fluid anti-solvent as it enters the particle formation vessel.  
     
     
         15 . The method of  claim 14 , wherein shock waves from the Mach disk propagate in the direction of the compressed fluid anti-solvent flow.  
     
     
         16 . The method of  claim 2 , wherein the compressed fluid anti-solvent is a supercritical fluid.  
     
     
         17 . The method of  claim 2 , wherein the fluid vehicle comprises two or more fluids which are mixed in situ at or immediately before their contact with the compressed fluid anti-solvent.  
     
     
         18 . The method of  claim 17 , wherein the two or more fluids each carry one or more substances that are to be combined in the particle formation vessel.  
     
     
         19 . The method of  claim 2 , wherein: 
 the compressed fluid anti-solvent, having a kinetic energy, disperses the substance in the fluid vehicle by transferring the kinetic energy from the compressed fluid anti-solvent to the fluid vehicle; and    the kinetic energy of the compressed fluid anti-solvent extracts the fluid vehicle from the substance.    
     
     
         20 . The method of  claim 2 , wherein the compressed fluid anti-solvent and the substance in the fluid vehicle contact each other immediately downstream of the point of compressed fluid anti-solvent entry into the particle formation vessel.  
     
     
         21 . The method of  claim 20 , wherein the contact between the compressed fluid anti-solvent and the substance in the fluid vehicle occurs between about 0.5 seconds and about 10 seconds of the compressed fluid anti-solvent entering the particle formation vessel.  
     
     
         22 . The method of  claim 21 , wherein: 
 the second fluid inlet has an outlet opening; and    the contact between the fluid anti-solvent and the substance in the fluid vehicle occurs at a distance from the compressed fluid anti-solvent entering the particle formation vessel of between about 10 and about 40 times a diameter of the outlet opening of the second fluid inlet.    
     
     
         23 . The method of  claim 21 , wherein the contact between the fluid anti-solvent and the substance in the fluid vehicle occurs at a distance from the compressed fluid anti-solvent entering the particle formation vessel of between about 2 mm and about 8 mm.  
     
     
         24 . The method of  claim 2 , further comprising providing controlled agitation within the particle formation vessel in the region of fluid contact.  
     
     
         25 . The method of  claim 31 , wherein the controlled agitation is selected from a list comprising sonication and stirring.  
     
     
         26 . The method of  claim 25 , wherein the stirring is selected from a list of stirring methods comprising a turbine, a propeller, a paddle, and an impeller.  
     
     
         27 . The method of  claim 2 , wherein the substance in the fluid vehicle is introduced directly into the flow of the compressed fluid anti-solvent.  
     
     
         28 . The method of  claim 27 , wherein the first fluid inlet terminates inside the flow of the compressed fluid anti-solvent coming out of the second fluid inlet.  
     
     
         29 . The method of  claim 2 , wherein the substance in the fluid vehicle and the compressed fluid anti-solvent meet, the angle between their axes of flow is between about 70° and about 110°.  
     
     
         30 . The method of  claim 2 , wherein the fluid vehicle comprises a fluid with a boiling point greater than about 150° C.  
     
     
         31 . The method of  claim 30 , wherein the pharmaceutical is salmeterol xinafoate, risperodone-(9-hydroxy)-palmitate, derivatives thereof, and combinations thereof.  
     
     
         32 . The method of  claim 6 , wherein P 1 , P 2 , T 1  and T 2  are selected so as to form particles of the substance having a volume mean diameter of less than 5 μm.  
     
     
         33 . The method of  claim 32 , wherein P 1 , P 2 , T 1  and T 2  are selected so as to form particles of the substance having a volume mean diameter of less than 1 μm.  
     
     
         34 . The method of  claim 6 , wherein P 1 , P 2 , T 1  and T 2  are selected so as to form particles of the substance having a size distribution with a standard deviation of 2.5 or less.  
     
     
         35 . The method of  claim 2 , wherein the compressed fluid anti-solvent contains one or more modifiers.  
     
     
         36 . The method of  claim 35 , wherein the one or more modifiers are selected from the group of water, methanol, ethanol, isopropanol, and acetone.  
     
     
         37 . The method of  claim 35 , wherein the one or more modifiers constitutes between about 1 mole % and about 40 mole % of the anti-solvent fluid.  
     
     
         38 . A method for preparing a substance in particulate form, the method comprising: 
 introducing into a particle formation vessel the substance in a fluid vehicle through a first fluid inlet, wherein the particle formation vessel has a pressure P 1  and a Temperature T 1 ;    introducing into the particle formation vessel a compressed fluid anti-solvent for the substance through a second fluid inlet, wherein the compressed fluid anti-solvent is introduced through a restricted inlet so as to have a back pressure of P 2  so that P 2  is greater than P 1 , wherein the compressed fluid anti-solvent has a temperature T 2  so that T 2  is greater than T 1 , and wherein T 1  and T 2  are such that Joule-Thomson cooling of the compressed fluid anti-solvent as it enters the particle formation vessel does not reduce temperature of the compressed fluid anti-solvent to below that required of it to produce particles; and    allowing the compressed fluid anti-solvent to extract the fluid vehicle from the substance to form particles of the substance, wherein the compressed fluid anti-solvent has a sonic, near-sonic or supersonic velocity as it enters the particle formation vessel, wherein the compressed fluid anti-solvent and the substance in the fluid vehicle enter the particle formation vessel at different locations and meet downstream in the particle formation vessel.    
     
     
         39 . A method for preparing a pharmaceutically active substance in particulate form, the method comprising: 
 introducing into a particle formation vessel the pharmaceutically active substance in a fluid vehicle through a first fluid inlet;    introducing into the particle formation vessel near-critical or supercritical carbon dioxide through a second fluid inlet; and    allowing the near-critical or supercritical carbon dioxide to extract the fluid vehicle from the pharmaceutically active substance to form particles of the pharmaceutically active substance, wherein the near-critical or supercritical carbon dioxide has a sonic, near-sonic or supersonic velocity as it enters the particle formation vessel, wherein the near-critical or supercritical carbon dioxide and the pharmaceutically active substance in the fluid vehicle enter the particle formation vessel at different locations and meet downstream in the particle formation vessel.