Process for improving crystallinity

Abstract

This invention provides a process for increasing the crystallinity of at least one solid material which is less than 100% crystalline, comprising contacting said solid material with solvent in which the solid material is insoluble or poorly soluble (a non-solvent); and applying ultrasound to the solid material when in contact with said non-solvent.

1 - 43 . (canceled) 
     
     
         44 . A particle being obtained by a process comprising contacting a solid material with solvent in which the solid material is insoluble or poorly soluble (a non-solvent); and applying ultrasound to the solid material when in contact with said non-solvent, wherein the particle comprises a pharmaceutically active ingredient which is tiotropium. 
     
     
         45 . A particle according to  claim 44  which has nanometer scale surface corrugations and the value for Rq is between 10 and 100 nm. 
     
     
         46 . A particle according to  claim 44  wherein the active ingredient is tiotropium bromide. 
     
     
         47 . A particle according to  claim 44  which has a crystallinity of greater than 90% by weight. 
     
     
         48 . A particle according to  claim 44 , wherein the average ratio of the largest diameter to the smallest diameter is 1.3-1:1. 
     
     
         49 . A particle according to  claim 44 , wherein the surface area of the particle is 6 to 22 m 2 /g. 
     
     
         50 . A particle according to  claim 44  wherein the surface area of the particle is 9 to 18 m 2 /g. 
     
     
         51 . A particle according to  claim 44  wherein the surface area of the particle is 10 to 13 m 2 /g. 
     
     
         52 . A particle according to  claim 44 , wherein the particle has a mass median aerodynamic diameter (MMAD) of less than 10 μm, preferably 0.05 to 5 μm, more preferably 0.05 to 2 μm. 
     
     
         53 . A particle according to  claim 44 , wherein the particle is obtained by applying ultrasound for a period of greater than 0.1 ms. 
     
     
         54 . A particle according to  claim 44 , wherein the particle is obtained by applying ultrasound to a solid material which contains less than 5% by weight of solvent. 
     
     
         55 . A particle according to  claim 44 , wherein the particle further comprises an active pharmaceutical ingredient, an active agrochemical ingredient, a pharmaceutical excipient, an agrochemical excipient or a mixture of two or more thereof. 
     
     
         56 . A particle according to  claim 44 , wherein the particle is obtained by a process comprising:
 (i) forming a solution of at least one solid material in a solvent;   (ii) subjecting the solution to a process selected from the group consisting of rapid precipitation, freeze drying, lyophilisation, rapid expansion of supercritical solutions, spray drying or mixtures thereof, wherein the said dissolved solid material is converted into a substantially dry solid material;   (iii) optionally isolating the solid material from the liquid and/or gaseous components of the process of step (ii);   (iv) treating said dry solid material from step (ii) or step (iii) with a non-solvent therefor;   (v) applying ultrasound to the solid material from step (iv) when it is in contact with said non-solvent; and   (vi) optionally separating and/or drying the resultant solid material from step (v).   
     
     
         57 . A particle according to  claim 56 , wherein the process is sequential, and steps (iv) and (v) take place immediately after step (ii). 
     
     
         58 . A particle according to claim  1 , wherein the frequency of the ultrasound waves is in the range of from 10-100 kHz. 
     
     
         59 . A particle according to  claim 44 , wherein ultrasound is applied at a power density of 100 W/L or less. 
     
     
         60 . A particle according to  claim 44 , further comprising a pharmaceutically active ingredient selected from the group consisting of anti-allergics, bronchodilators, anti-inflammatory steroids and mixtures thereof. 
     
     
         61 . A particle according to  claim 44 , further comprising a pharmaceutically active ingredient suitable for use in an inhalation formulation, preferably, budesonide, salbutamol, formoterol or mixtures of two or more thereof. 
     
     
         62 . A pharmaceutical composition comprising particles according to  claim 44  and further comprising carrier particles, the carrier particles being preferably selected from lactose, glucose and hydrates thereof. 
     
     
         63 . A pharmaceutical composition according to  claim 62 , wherein the cohesive-adhesive balance ratio of the particles with the carrier particles is 0.8 to 1.3. 
     
     
         64 . A dry powder inhaler, pressurized metered-dose inhaler (pMDI) or a breath activated nasal inhaler containing a pharmaceutical composition according to  claim 62 .