(539b) An Engineering Approach to Concentration of Temperature-Sensitive Pharmaceutical Process Streams for Continuous Crystallization of an API

Roche, P. - Presenter, Synthesis and Solid State Pharmaceutical Centre (SSPC), School of Chemical & Bioprocess Engineering, University College Dublin
Pascual, G. K., University College Dublin
Jones, R., University College Dublin
Donnellan, P., University College Dublin
Glennon, B., University College Dublin
An Engineering Approach to Concentration of Temperature-Sensitive Pharmaceutical Process Streams for Continuous Crystallization of an API


P. Roche1, G.K. Pascual1, R. C. Jones*1, P. Donnellan*1, and B. Glennon1

1 Synthesis and Solid State Pharmaceutical Centre (SSPC), School of Chemical and Bioprocess Engineering, University College Dublin, Belfield, Dublin 4, Ireland

Keywords: Solution Concentration, Continuous Processing, Bubble Column, Crystallization, MSMPR, PAT Technologies



Traditionally, most active pharmaceutical compounds (API) have been manufactured at large plant scales using batch methodologies. Continuous manufacturing is becoming an increasing attractive alternative due to apparent benefits such as smaller manufacturing footprints, increased process safety, lower manufacturing costs and increased supply-chain flexibility. [1] A common problem faced in small molecule API production is the necessity for concentration steps between unit operations i.e. where the upstream process (e.g. reaction) is fully developed at a given concentration of solution; while the downstream process (e.g. crystallization) is operated at a different concentration range, driven by the metastable limits of the crystallisation process. To date, concentration steps have been carried out as evaporative crystallisation, i.e. boiling off a known amount of solvent until a desired concentration is reached. [2] However, some APIs have shown signs of degradation at high temperatures. [1]This study aims to provide a low temperature method under ambient pressure for concentration of API solvent solutions.

Section 1 – Solution Concentration: A Novel Approach

This section of work focuses on employing a simple, lab-scale bubble column as a gas-liquid contacting system to achieve a desired removal rate of solvent. A model-based, mass transfer rate prediction is shown and compared with experiments performed for several common solvents used in the pharmaceutical industry. Thermodynamic predictions of Vapour-Liquid Equilibria were used in conjunction with mass transfer coefficients to accurately predict the rate of removal of solvent for the system and verified experimentally.[2]

For this work, a solution of Paracetamol in Methanol was chosen as the process, due to the well-researched saturation limits of paracetamol [3]and the reasonable results obtained from previously studied trials with methanol solutions in the column. The solution was reduced to an optimum concentration for the proceeding step from a dilute feed, while assuring that nucleation would not occur in any of the transfer lines by operating safely within the saturation limits.

Section 2 – Continuous Crystallization Optimization

Following the establishment of model predictions, the column was employed immediately upstream of the feed of a continuously operated mixed suspension, mixed product removal (MSMPR) crystallizer with intermittent withdrawal via dip pipe [4, 5]using an automated pressure supply for the cooling crystallization of paracetamol in methanol. In-situ Focused Beam Reflectance Measurement (FBRM G400, Mettler Toledo) was used for real-time monitoring of chord length distribution and to accurately ascertain the point at which steady state operation had been reached; while in-situ PVM (ParticleView V819, Mettler Toledo) provides microscopy quality images in real time to monitor the crystal habit.

The overall objective of the work was to enable the adjustment of crystallization parameters, based on the optimum concentration provided by the gas-liquid contacting system, and to provide robust prediction of the crystallizer performance. Simple extraction of growth and nucleation kinetics from the MSMPR at steady state was accomplished using the population balance model.


1. Rawat, T. and I.P. Pandey, Forced Degredation Studies for Drug Substances and Drug Products - Scientific and Regulatory Considerations. Journal of Pharmaceutical Sciences and Research, 2015. 7(5): p. 238-241.

2. Sandler, S., Other Types of Phase Equilibria in Fluid Mixtures, in Chemical, Biochemical and Engineering Thermodynamics. 2006, John Wiley & Sons, Inc. p. 575-593.

3. Granberg, R.A. and A.C. Rasmuson, Solubility of Paracetamol in Pure Solvents. Journal of Chemical Engineering Data, 1999. 44: p. 1391-1395.

4. Power, G., et al., Design and Optimization of a Multistage Continuous Cooling Mixed Suspension, Mixed Product Removal Crystallizer. Chemical Engineering Science, 2015. 133: p. 125-139.

5. Morris, G., et al., Estimation of Nucleation and Growth Kinetics of Benzoic Acid by Population Balance Modeling of a Continuous Cooling Mixed Suspension, Mixed Product Removal Crystallizer. Organic Process Research & Development, 2015. 19(12): p. 1891-1902.