Friday, August 21, 2015

Use kinetic models to obtain conservative estimates of TMR (time to maximum rate)

Readers with an interest in process safety (isn't that everyone?) should be aware of some important limitations in the traditional method for obtaining TMR, the time to maximum rate, as referenced here, for example.

Wilfried Hoffmann, one of our principal consultants supporting users and an experienced former specialist in process safety at Pfizer, highlighted in his December 2014 DynoChem webinar how:

  1. the traditional approach to TMR using MTSR (maximum temperature reached as a result of adiabatic temperature rise of the desired reaction, after a cooling failure) ignores the kinetics of the desired reaction; that makes it simple, but potentially less accurate; this is understandable as when the method was developed, kinetics were less readily obtained
  2. the traditional method neglects the time to MTSR in calculating TMR and time to explosion
  3. the modern method uses kinetics to get the true TMR
  4. there are two extremes where the difference between traditional and modern methods is significant:
    • with a slow reaction, perhaps taking place at low temperature, it may take a long time to reach MTSR; in this case, traditional TMR < true TMR and the traditional method may be used safely; it overestimates risk
    • in situations where on the way to MTSR, there is a heat flow contribution from the undesired reaction, the adiabatic temperature rise will then be higher than MTSR and the true TMR will be shorter than the estimate using the traditional method.

You can watch a preview of Wilfried's discussion on YouTube.  You can also read more in his book chapter here.

Needless to say, we recommend that you use kinetic information to calculate TMR, so that you can make stronger safety statements.  If you have access to DynoChem and our online library, follow this link to find the main tools, step by step training and a nice customer case study by Siegfried.

Slide from Wilfried Hoffmann's webinar, illustrating response surfaces of true TMR, obtained from kinetic models of the desired and undesired reactions.

Thursday, August 20, 2015

Continuous improvement, with enhanced tools and guidance for PFR, CSTR and axial dispersion models

Readers will doubtless be aware of the momentum behind the move to continuous manufacturing of pharmaceuticals and the "Need for enhanced process understanding ...Availability of mechanistic models for all processing steps".  We frequently support customers either exploring or making the transition from batch to continuous and there are many case studies available showing how to use DynoChem in this context.

In the August update of our online library, we added new guidance documents on how to apply the platform tools in this area.  Separate documents address PFR, CSTR and PFRs with axial dispersion. We also enhanced each of the models and the training exercises that step you through an application.

For those who are interested in connecting models together in a flowsheet simulation, we set up a few examples illustrating how to do this and these are available to certified and power users on request from our support team.
Substrate concentration versus residence time for second order reaction with 5% excess.  Comparison of ideal PFR with tanks-in-series models representing different degrees of backmixing / axial dispersion.
We'd be glad to receive your feedback in due course on all of the above.

Wednesday, July 29, 2015

Kinetics from HPLC data - DynoChem guidance documents

HPLC area and area percent are some of the most commonly used data for reaction and impurity profiling and monitoring.  Customers collect these data all the time, whether working in the lab or the plant, in early or late phase development.  HPLC data are routinely used in regulatory filings and to ensure quality and compliance.

The good news for DynoChem users is that reaction kinetics may also be obtained from these data, when certain conditions are met.  Yes, there is some fine print, but not too much.  Armed with kinetics, you can run fewer, better experiments and save weeks or months of experiments and speculation.  (You might enjoy our playlist of short humorous videos on this very topic.)

In this and several other application areas, our team have recently written new 'Guidance Documents'. These follow a standard format and are short and to the point.  They provide a helicopter view and a roadmap for applying DynoChem in a specific application area.  Naturally the guidance document for reaction kinetics puts a lot of emphasis on HPLC data.  You can get the full story by following this link.

Contents page of the Reaction Modeling Guidance Document: click for step by step instructions.

Wednesday, July 8, 2015

Generate cocrystal ternary phase diagrams to support process design

We love to provide solutions that save customers time.  A good example arises in process and experimental design aimed at formation of cocrystals.

DynoChem already includes tools to support solvent selection for crystallization and these can indicate the effects of solvent choice on API ("A"), coformer ("B") and cocrystal ("AB") solubility, based on a handful of measurements in a few solvents.  We also provide templates for solution-mediated conversion between forms and drug product salt disproportionation in the presence of excipients.

For cocrystals, once solubilities are known, either by measurement or prediction, a DynoChem dynamic model can simulate in a few seconds the time-dependent equilibration of a large set of potential experiments, reducing the need for painstaking and slow lab experimentation.

Figure 1: Process scheme for simulating cocrystallization process; more solid phases may be included as needed

With this model, users can simulate the relative and total amounts of each of the (e.g. three) solid phases that may result from different starting conditions.  Those results can be plotted and summarized on a ternary phase diagram that summarizes the 'regions' of initial composition that lead selectively to formation of the desired phase.

Figure 2: Ternary phase diagram for an example cocrystal system, with a 1:1 cocrystal AB.

Contact if you'd like to discuss using these tools, or related applications to enantiomers and other systems.  Thanks to Dr Andrew Bird for providing the above illustrations.  

Monday, June 29, 2015

Sarah Rothstein of Nalas Engineering: Design a continuous flow process using batch lab data

This webinar from our 2014 series features a fine example of using modeling to get insight without committing resources.  Sarah Rothstein and her colleagues at Nalas Engineering used DynoChem to design a continuous process using batch experiments and found optimum operating conditions without running any experiments in the 'flow' system.

Invest 7 minutes to see what good users can do with our tools:

If you'd like instead to see the full version of Sarah's webinar, follow this link to DynoChem Resources.

Friday, June 19, 2015

DynoChem Spray Dryer model calculates thermodynamic Design Space

When planning to select or use a spray dryer in the lab or at larger scale, it's important to know the right operating conditions (feed rate, gas inlet temperature, pressure) to achieve potential critical quality attributes like residual moisture and gas outlet temperature.  You can map your dryer's operating space easily using the DynoChem spray dryer template, reducing your dependence on trial and error to find the right process conditions.

Results can be generated for any solvent system in a few minutes.  You can also fit the heat loss parameter (UA) to better characterize your dryer.  And fit the gas-liquid mass transfer parameter (kLa) if your system does not reach equilibrium.

Wednesday, June 10, 2015

June update adds models for genotoxic impurity formation and control, precipitation, PK/PD and more

One of the great things about using DynoChem is the regular update of the online library, delivering the latest and best models to all users instantly.

Blood pressure regulation in a specific patient using a 200mg daily dose.
In the June update:

  • We published a new guidance document for solvent swap distillation, a very popular DynoChem application. 
  • We added new models for sulfonate ester / genotoxic impurity formation (based on work using DynoChem by Dr Ed Delaney and a PQRI consortium)
  • We added new models for tangential flow filtration (TFF), precipitation and PK/PD calculations. 
  • We republished the DynoChem Validation document, illustrating the accuracy of each DynoChem model building statement. 
  • We updated our solvent properties shortlist, adding three solvents (1-propanol, isobutanol and trifluoroacetic acid) 
  • We updated a number of models to the new standard format.
To try them out, visit DynoChem Resources.

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