Process for the manufacture of powders of inhalable medicaments

Abstract

The invention relates to an improved process for the production of powders of an inhalable medicament by crystallization from a supersaturated fluid containing said medicament, the method comprising passing along a tubular reactor (a) a segmented flow of that fluid comprised of discrete volumes; or (b) a fluid mixture being separated by discrete volumes of a separating fluid which is substantially immiscible with said fluid, characterized in that the crystallization is initiated by application of ultrasound

What is claimed is:  
     
         1 . An improved process for the production of powders of inhalable medicaments by crystallization from a supersaturated fluid containing said medicament, the improved process comprising passing along a tubular reactor 
 (a) a segmented flow of a supersaturated fluid containing medicament comprised of discrete volumes; or    (b) a fluid mixture being separated by discrete volumes of a separating fluid which is substantially immiscible with the supersaturated fluid containing medicament,    and initiating crystallization by application of ultrasound.    
     
     
         2 . The process as claimed in  claim 1  wherein the segmented flow passes along the tubular reactor as a plug flow.  
     
     
         3 . The process as claimed in  claim 1  wherein the tubular reactor consists of the following segments: 
 (i) a residence time (t R ) segment;  
 (ii) an ultrasound time (t US ) segment; and  
 (iii) optionally an aging time (t A ) segment.  
 
     
     
         4 . The process as claimed in  claim 3  wherein t US  is 1 to 30 s and t A  is 0.5 to 15 min.  
     
     
         5 . The process as claimed in  claim 3  wherein t US  is 0.5 to 15 min and t A  is 0 to 30 s.  
     
     
         6 . The process as claimed in  claim 1  wherein ultrasound with a frequency of 20 to 60 kHz is applied.  
     
     
         7 . The process as claimed in  claim 6  wherein the energy density of the ultrasound applied is from 10 to 80 WL −1.    
     
     
         8 . A micro-reactor for implementing the process according to  claim 1  comprising a micro-mixer, a segmenter and a tubular reactor, wherein 
 the dimensions of the micro-mixer for dividing the added fluids which are to be mixed is in the range of 10 μm to 1 mm, preferably between 25 μm to 200 μm,  
 the dimensions of the channels of the segmenter lie in the range of 0.1 to 5 mm, preferably in the range of between 0.2 mm and 5 mm, and  
 the tubular reactor is configured to be tube-, pipe- or channel-shaped with diameters of the channels in the range of 0.5 to 10 mm, preferably 1 mm to 2 mm, and with a length of between 10 cm and 200 m, preferably between 1 m and 25 m and is equipped with an external ultrasound source.  
 
     
     
         9 . The micro-reactor according to  claim 8 , wherein the tubular reactor consists of the following segments: 
 (i) a residence time (t R ) segment;    (ii) an ultrasound time (t US ) segment; and    (iii) optionally an aging time (t A ) segment.    
     
     
         10 . The micro-reactor according to  claim 9 , wherein the ultrasound time (t US ) segment is inserted into an ultrasound bath.  
     
     
         11 . An inhalable medicament with an aerodynamic diameter of less than 20 μm, preferably less than 5 μm and greater than 0.3 μm, characterized in that it is produced by means of a process according to  claim 1.