Interaction between chemical reactions and mixing on various scales

Interaction between chemical reactions and mixing on various scales is an important topic in both industrial applications and education.  Our colleague at Scale-up Systems, Dr Steve Hearn, authored a paper of this title in 1997, on completion of his PhD with Professor John Bourne and Professor Jerzy Baldyga (their subsequent book available here).

Steve's paper demonstrated the importance of 'mesomixing' for chemical reactions with fast kinetics and has been cited heavily when this concept has been applied since that time to reaction and crystallization systems, for example.

Steve's PhD included measuring and modeling 'Bourne' reactions (azo-couplings of 1- and 2-naphthol) in a Kenics static mixer and varying the flowrate / energy dissipation and fluid viscosity.  These were some of the first models we included in DynoChem and the figure below shows comparison of measured and predicted 'XQ' values.  Low XQ (side-product formation) corresponds with faster mixing.

In addition to template models containing the competing chemical and mixing time constants as parameters, we also included 'utilities' so that user can quickly estimate the time constants from reactor geometry, operating conditions and feed position/ rate.  And together with Professor Bourne and other leading authorities on mixing, we built a range of knowledge base articles from which users can learn all about it.

We will return to this topic in subsequent posts on DynoChem Resources online library models that apply these concepts to predict mixing effects in a range of systems.

Update 68 to the DynoChem online library features crystallization, filtration and bioreaction tools and content

Update 68 of the DynoChem Resources online library took place today, including:

• New Crystallization tab in statements.xls, covering kinetic modeling of crystallization from solubility and MZW definition, through temperature-dependent growth to population balance models with linear or log spaced channels
• Customer requested updates to the industry's best solubility tools, making them easier to use, with CAS Number references in the solvent selection tool and the ability to move your preferred late phase solubility expression into other workbooks for hand calculations.
• Minor updates to improve ease of use in the filtration model and new content on modeling drying using DynoChem
• Slides from recent guest webinar by Dr Gearoid Duane on bioreaction modeling.

You can see a full list of changes in the WhatsNew document.
To try out the tools and content log in at https://dcresources.scale-up.com/.

Predicted effect of residence time and operating temperature on particle size from a CSTR crystallizer

Begin with the end in mind: how to obtain equivalent results at different scales

The impact of physical processes on the performance of manufacturing operations is well known.  Good accounts of the basic problem are available in many textbooks, such as that of Zlokarnik, Atherton & Carpenter and many more. Regulators understand this too, with the word 'scale' appearing 25 times in ICH Q11, with statements like "The development ... should account for scale effects and be representative of the proposed commercial process".

It is remarkable then that much airtime is given to laboratory scale statistical design of experiments as a vehicle for efficient process development, without adequate discussion of how the DOE results can be made scalable.  The good news for the drug substance / API synthesis community is that the necessary concepts for scalability are well established and can be put into practice with DynoChem software tools that are easy to use.   You can for example achieve equivalent 'mixing' between 100 mL and 1500 L reactors, or match addition times / cooling rates between lab and plant, by investing 15 minutes of your time.  Doesn't that beat having to deal with missed deadlines or increased impurity levels on scale?  And the associated process rework?

We made a carton animation to raise awareness of the problem and the opportunity.  If you see the potential, sign up for DynoChem access.

DynoChem Resources Update 67: Calculate vortex shape and baffle effects in vessel mixing utilities

Update 67 in November 2013 focused on the DynoChem mixing / vessel utilities, enhancing them to include detailed definition of baffle type and number and the associated calculations of vortex shape, wetted area and agitator power. To find out more:

• Download the KB Article describing the new calculations of vortex shape and baffle effects in the vessel / mixing utilities:https://dcresources.scale-up.com/Default.aspx?id=364
• Watch the recorded webinar: http://dcresources.scale-up.com/Recording.aspx?id=932

DynoChem web library update #66, September 2013: Drug dissolution models, slides from guest webinars, KB articles and enhancements

We update the DynoChem Resources (‘DCR’) website monthly with new tools/ applications and content that are immediately available to all users.  These updates and other news are announced on Twitter and you can keep up to date anytime by following us.

You can always stay up to date using the comprehensive WhatsNew.pdf summary.  

Update 66 this month included:

·         Slides from recent DynoChem guest webinars by customers from BMS, Merck and Reaction Science

·         New models for simulation of drug dissolution in a USP Apparatus:

o   under monophasic or biphasic (sink) conditions, for BCS Class II compounds

o   with competing disintegration and dissolution rates for immediate release formulations

·         New syntax in statements.xls for defining common reactions with SN1 or SN2 mechanisms, acid catalysis, pH variations and working with HPLC Area Percent data

·         New branches in the training tree for building a model step by step and then moving to consider process safety issues on scale-up

·         New KB articles and webinar recordings on use of HPLC data to build DynoChem models.

We hope that you find this update useful and will forward/ share it within your own organization with people who may be interested. 

Please note that we have upcoming public training events for New Users in Wilmington and San Francisco.

For the record, Updates 63-65 in the last 3 months included:

·         a whole new Library of flow chemistry models, with training and a PFR design utility;

·         new models for reactions (using carbonate base, Suzuki Coupling, optical resolution);

·         new calculations in the VLLE utility (ternary boiling point, mixture flash point);

·         new recorded webinars (e.g. BMS on QbD and Merck on extending the benefits of modeling across a department).

Boston Training: Get Started with Process Optimization and Scale-up using DynoChem (at Cambridge Residence Inn, Kendall Square)

Join the DynoChem training team for two days of hands-on training, using DynoChem to accelerate process development and scale-up projects.

Training will address DynoChem applications for engineers and scientists in API process development groups involved in tech transfer, troubleshooting and optimisation of API reaction, workup and isolation steps.  

The agenda will cover topics such as:

• Obtaining physical property values for solvents and mixtures
• Phase equilibrium calculations for boiling point, identifying azeotropes and miscibility
• Reactor calculations for heat transfer and mixing
• Optimising batch distillation / solvent switch operations
• Scale-up of filtration and centrifugation steps
• Basics of DynoChem modelling applicable to reactions, crystallization and other operations

Training times will be from 9:00 to 4:30 each day, with 6 hours of tuition.  Computers with DynoChem installed may be provided for your convenience - let us know if you will be needing one and we will confirm the cost. 

Learning objectives:

By the end of the course, trainees will be able to:

• Draw and understand process schemes and use them to help think about how to model or design experiments to understand a new or existing process
• Use DynoChem utilities to estimate parameter values, compare vessels and ensure minimum agitation criteria are met in lab and plant vessels
• Model chemical reactions, including kinetics, temperature-dependence, reaction orders
• Fit chemical kinetics to typical lab data
• Optimise reactions for yield and impurity levels
• Generate response surfaces to study process robustness and determine design space for QbD submissions
• Further develop initial models to include multi-phase, scale-up and interpretation of analytical data
• Use plant data to back out equipment characteristics, especially heat transfer
• Simulate solid-liquid separation operations based on standard lab experiments
• Look up physical properties for pure components and mixtures
• Simulate solvent swap / displacement / chasing operations to optimize solvent volumes and cycle time
• Understand more about how DynoChem works internally and how it builds the model from user input

• Explore other applications and reuse learned skills to tackle other unit operations or create new templates.

Event Registration Online for Boston Training: Get Started with Process Optimization and Scale-up using DynoChem powered by Eventbrite

And now, for something a bit different

If you are a regular on our YouTube Channel, you'll know that we go into technical detail when talking about using our software to support chemical development, scale-up and QbD.

Today we posted a 1-minute video cartoon animation that you may find amusing, interesting and helpful in explaining the potential of DynoChem to your colleagues.

If you like it, let us know by sharing it, emailing us, or the next time we see you.