(381e) Controlling Crystal Size Via Fine Particle Dissolution in a Closed Loop Wet Milling Crystallization

Authors: 
Ramisetty, K., University of Limerick
Croker, D., Bernal Institute, University of Limerick
Rasmuson, A., KTH Royal Institute of Technology
Cote, A., Merck

Controlling
Crystal Size via Fine Particle Dissolution in A Closed Loop Wet Milling
Crystallization

Kiran Ramisetty1, Denise Crocker1,
Aaron Cote2, Tom O'Ceallaigh3, Ake Rasmuson1

1.      
Department
of Chemical and Environmental Science, Synthesis and Solid State Pharmaceutical
Centre, Materials and Surface
Science Institute,
University of Limerick, Limerick, Ireland.

2.      
Merck
& Co., Inc. (2000 Galloping Hill Road, Kenilworth, New Jersey, USA 07033.

3.      
Meck
& Co., Inc., Ballydine, Kilsheelan, Clonmel Co Tipperary, Ireland.

Controlling crystal
size in pharmaceutical industry is a challenging task; several approaches has
been used to produce crystals with narrow crystal size distribution. One of the
novel technique is integrating a wet mill to the crystallizer in order to break
the crystals in the suspension1. However, this method often produces
particles with more number of fines. In the presentation, we will show how the
crystal size with a narrow distribution can be obtained via wet milling of the
suspension from a crystallizer (CR) followed by fines dissolution in a separate
crystallizer (CD - crystal dissolver) which is maintained at a higher
temperature than CR and followed by slow cooling to grow the crystals for
better yield. We will also show how the particle size produced from milling can
be altered or controlled through optimization of the number of milling cycles,
milling speed and the initial properties of the crystals (shape and size). To study
this, different size crystals produced from CR by generating different supersaturation
regimes via varying parameters such as cooling rate, antisolvent addition rate and
initial amount of the solute. Additionally, different shape of the crystal
produced with different solvent. Both the reactors were equipped with process
analytical techniques like FBRM, ATR-FTIR and PVM.  Change in crystal size and number continuously
monitored with FBRM in crystallizer and dissolver to understand the
crystallization and dissolution kinetics. ATR-FTIR used to monitor the change
in concentration during dissolution and growth phases in the dissolver.  This work will also show the possibility to implement
batch process to continuous crystallization with integrated milling and dissolution
to produce narrow crystal size distribution.  

References:

1.      
Yang Yang, Liangcheng Song, Tianyue Gao, and
Zoltan K. Nagy Integrated Upstream and Downstream Application of Wet
Milling with Continuous Mixed Suspension Mixed Product Removal Crystallization,
Cryst. Growth Des. 2015, 15, 5879−5885

This work has been supported by
Science Foundation Ireland, Grant number: 12/RC/2275.