Continuous Crystallization of Cyclosporine: Effect of Operating Conditions on Yield and Purity

A continuous crystallization process has potential advantages such as lower cost and improved flexibility in pharmaceutical production when compared to batch crystallization. In this work, multistage continuous cooling crystallization processes for cyclosporine were developed. The approach demonstrated that optimization of stage conditions can be used to improve yield and purity. For a multi-impurity system such as cyclosporine, the segregation of each impurity should be estimated separately due to their different behaviors. The effective distribution coefficients of the impurities were calculated and related to the steady state mother liquor concentrations. A population balance and mass balance model including distribution coefficients for impurities was used to estimate maximum yields and purities that could be obtained at various operating conditions. The results showed the limitation in yield and purity improvement using a mixed-suspension, mixed-product removal cascade. In addition, optimization alon...

[1]  P. Vekilov,et al.  Distribution coefficients of protein impurities in ferritin and lysozyme crystals Self-purification in microgravity , 2000 .

[2]  Zoltan K. Nagy,et al.  Fines removal in a continuous plug flow crystallizer by optimal spatial temperature profiles with controlled dissolution , 2013 .

[3]  Narayan Variankaval,et al.  From Form to Function: Crystallization of Active Pharmaceutical Ingredients , 2008 .

[4]  Allan S. Myerson,et al.  Continuous Plug Flow Crystallization of Pharmaceutical Compounds , 2010 .

[5]  Richard D. Braatz,et al.  Advanced control of crystallization processes , 2002, Annu. Rev. Control..

[6]  K. Sangwal,et al.  On the supersaturation and impurity concentration dependence of segregation coefficient in crystals grown from solutions , 2000 .

[7]  P. Poechlauer,et al.  Continuous Processing in the Manufacture of Active Pharmaceutical Ingredients and Finished Dosage Forms: An Industry Perspective , 2012 .

[8]  Allan S. Myerson,et al.  Crystallization of Cyclosporine in a Multistage Continuous MSMPR Crystallizer , 2011 .

[9]  Ronald W. Rousseau,et al.  Distribution of Isomorphic Amino Acids between a Crystal Phase and an Aqueous Solution , 2002 .

[10]  Allan S. Myerson,et al.  Continuous Crystallization of Aliskiren Hemifumarate , 2012 .

[11]  Allan S. Myerson,et al.  Development of Continuous Anti-Solvent/Cooling Crystallization Process using Cascaded Mixed Suspension, Mixed Product Removal Crystallizers , 2012 .

[12]  Allan S. Myerson,et al.  Control of Polymorphism in Continuous Crystallization via Mixed Suspension Mixed Product Removal Systems Cascade Design , 2015 .

[13]  James M. B. Evans,et al.  End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation. , 2013, Angewandte Chemie.

[14]  Zoltan K. Nagy,et al.  Recent advances in the monitoring, modelling and control of crystallization systems , 2013 .

[15]  Dimitrios I. Gerogiorgis,et al.  Economic Analysis of Integrated Continuous and Batch Pharmaceutical Manufacturing: A Case Study , 2011 .

[16]  S. Y. Wong,et al.  Development of Continuous Crystallization Processes Using a Single-Stage Mixed-Suspension, Mixed-Product Removal Crystallizer with Recycle , 2012 .

[17]  Ronald W. Rousseau,et al.  Effect of relative solubility on amino acid crystal purity , 2001 .

[18]  B. Trout,et al.  Multistage Continuous Mixed-Suspension, Mixed-Product Removal (MSMPR) Crystallization with Solids Recycle , 2016 .

[19]  Christopher L. Burcham,et al.  Regions of attainable particle sizes in continuous and batch crystallization processes , 2014 .

[20]  Gerry Steele,et al.  Continuous Crystallization of Pharmaceuticals Using a Continuous Oscillatory Baffled Crystallizer , 2009 .

[21]  Richard D Braatz,et al.  Advances and new directions in crystallization control. , 2012, Annual review of chemical and biomolecular engineering.

[22]  Richard D. Braatz,et al.  Application of Continuous Crystallization in an Integrated Continuous Pharmaceutical Pilot Plant , 2014 .