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How to access differentiated API particle populations through continuous technologies

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Microscope images of particles obtained from the multistage MSMPRC combined with wet milling

For the synthesis and crystallization of APIs the application of multistage Mixed Suspension Mixed Product Removal Crystallizers (MSMPRCs) can be beneficial in addressing common problems encountered in batch production. The work conducted here focuses on two case studies concerning the combination of wet milling with multistage (MSMPRCs) to improve the physical properties of the respective APIs.

1st Case Study: Standard Batch Process

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Standard Batch Process

Limitations of batch

  • Particles exhibit thin needle morphology

  • Changing various operating conditions yielded no significant results and so continuous crystallization was employed to try to improve particle aspect ratio

Continuous Crystallization Setup

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Images of the feed tanks and crystallization cascade combined with in-situ wet milling

Various challenges were met when performing the cooling crystallization in the multistage MSMPRC such as crystallization in the feed lines due to temperature drops between feed tanks and crystallizers. This was circumvented by employing heat exchangers on the feed lines.

Kinetic limitations

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FBRM trends for continuous crystallization in the absence of wet milling

Issues encountered

  • Steady state was not reached after days of operation as the system does not retain consistent particle population

  • Level of nucleation not sufficient to maintain a set population of particles in the crystallizer

Effect of wet milling
Benefits of in-situ wet milling:

  • Accelerates the nucleation rate due to increased turbulence within the crystallizer

  • Enables particle attrition which helps to improve the particle aspect ratio

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FBRM trends of the continuous crystallization process starting from a clear solution indicating that the nucleation rate has been accelerated

Improvement in final product
Improvement in final product assessed through examination of the aspect ratio of the particles via microscope.

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Microscope images of particles obtained from the multistage MSMPRC combined with wet milling

2nd Case Study: Standard Batch Process

Issues with standard batch process

  • Accessible particle size well in excess of formulation specification of50 < D50 [um] < 100

  • Forecast for API demand exceeded free batch plant capacity for manufacture

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Images illustrating standard batch process (top left), PSD output from batch (top right) and microscope image of batch product

Continuous Crystallization Setup

Continuous cooling crystallization performed in cascaded MSMPRCs. In the absence of wet milling, the crystallization ran smoothly and steady-state was attained readily.

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Image of two-stage MSMPRC and Trends showing sustained operation at steady-state

Kinetic Limitations

  • Minimum particle size achievable based on the kinetics of the system

  • Particle size could only be reduced to a D50 of 290µm

  • In-situ wet milling required to deliver desired D50 size specification of 50-100µm

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PSD corresponding to the minimum particle size achievable in the system based on the kinetics alone

Optimized Process and Final Product

  • Operating the two-stage MSMPRC with a first stage temperature of 18°C and a second stage temperature of 15°C with 5 minute residence times in each stage and a mill speed 16000rpm enabled sustained operation

  • Milling in stage 2 circumvented fouling issues and a product with a D50 of approximately 75µm was isolated

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Microscope image of the final product and PSDs from the process with and without milling


  • Robust platforms combining cascaded MSMPRCs and wet milling were developed for the production of two APIs

  • The particle aspect ratio was improved significantly in Case Study 1 through use of the developed platform

  • The particle size of the product in Case Study 2 met the formulation requirements and the production rate was also increased through continuous manufacturing

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