Streamlining Process Development and Chemical Synthesis DoE

A Design of Experiments (DoE) approach is often used by Process Development chemists while attempting to create safe, efficient, reproducible and cost-effective synthetic routes. DoE helps to determine the factors vital to achieving ideal reaction conditions with the help of a multivariate approach.

The experimental setup can also affect the process development chemistry. In conventional systems, a round bottom flask including heating-only equipment is often used for small-scale synthesis. However, such systems exhibit poor temperature control, which can usually result in inaccurate results and can impact the timeline and scale-up cost.

This article follows Purolite’s Process R&D group who aimed to enhance the quality and speed of their process development through an alternative parallel chemistry setup for accurate temperature control: the Mya 4 Reaction Station from Radleys.

Image credit: Purolite

Process development chemistry includes the development, scale-up and optimization of a chemical synthetic route for the purpose of transforming a compound into a commercial product.

The process chemist's objective is to develop synthetic routes that are cost-effective, safe, efficient and reproducible. For these reasons, the process chemist utilizes route scouting (i.e., determining the best synthetic route), then identifying the key factors (e.g., temperature or reactant concentration) of the selected chemical reaction.

This is to improve the safety, reliability and efficiency of the chemical reaction, as well as the yield and purity of the product, and eventually lead to considerable reductions in both time and cost. Establishing the main factors for a specific process has typically been focused on varying one factor at a time. This practice has many drawbacks.

Firstly, reaction outputs are extremely dependent on the early starting factors, which are evaluated and approximated by process development scientists and therefore influenced by researcher bias.

Secondly, the interactions across various factors are hard to determine because of the nature of only changing one factor at a time. Finally, it is difficult to identify genuine improvements from innate run-to-run variation unless a significant number of reactions are carried out.

Once the major factors have been identified using small-scale reactions, the process is then converted to large-scale reaction vessels for manufacturing use.

However, the limitations of the "one factor at a time" approach often results in the realization that the key factors determined from the small-scale reactions create out-of-spec products at the manufacturing level.

Further optimization studies at larger scales are then needed, typically resulting in a prolonged and expensive development process.

Recently, process development and optimization have moved towards statistical methods. By inserting statistics into the planning, conducting and data analysis of a reaction, systematic and effective decisions can be made.

This methodical approach can yield rapid, efficient and accurate process development, producing products with limited variability and defects as well as significantly lowering the translation time from small-scale chemistry to large-scale reactions at manufacturing plants.

The experimental setup is one of the main factors when aiming to conduct high-quality process development chemistry.

Conventional systems utilize a round bottom flask (RBF) and a hot plate/water bath, but they are liable to poor temperature control, which can often result in erroneous results which impact scale-up cost and timeline.

The approaches needed to improve the speed and quality of process development chemistry utilizing parallel synthesis and an alternative synthetic chemistry setup are outlined below in a case study from the Process Development group at Purolite in Llantrisant (Wales, UK).

Design of experiments (DoE) - A statistical approach to process development

Design of experiments (DoE) is one statistical approach for process development. It determines the key factors needed to achieve prime conditions for a product utilizing a multivariate approach.

In contrast to the conventional one factor at a time approach, DoE has significant advantages:

  • It optimizes knowledge while using the minimum number of resources possible; it offers accurate and efficient information.
  • Interactions between factors can be identified.
  • The importance of each factor can be characterized.
  • The process behavior can be predicted prior to experimentation.
  • Cause and effect relationships between key factors and responses can be identified.
  • A proven acceptable range of critical responses can be identified.
  • Simultaneous optimization of multiple responses can be acquired.
  • Outliers or anomalous data can be recognized effortlessly.
  • A robust production process can be achieved.

There are a number of steps that must be followed sequentially to accomplish a successful, high-quality DoE study.

Firstly, the objectives should be defined clearly. Here, the product profile is generated using the technical knowledge of the process development scientist in conjunction with scientific literature.

Secondly, a variety of input factors that are believed to influence the reaction process is identified. General factors include addition rate, raw material concentration, temperature, stirring speed, catalyst type or amount and pH. In this step, the main responses are also determined, such as selectively, yield and impurity level (Figure 1).

 

Schematic example of a DoE process.

Figure 1. Schematic example of a DoE process. Image Credit: Radleys

About Radleys

Radleys, world leaders in innovative productivity tools for chemists. Radleys provide innovative chemistry equipment for safer, cleaner, greener and more productive chemical research.

Radleys have been manufacturing scientific glassware and laboratory instruments for over 50 years and our customers include leading blue-chip industrial and academic research facilities around the world.

  • Established in 1966
  • Based in Saffron Walden, United Kingdom
  • Instrument and glassware manufacturer
  • In-house Research and Development facilities
  • Distributors in 47 countries

Our areas of expertise are focused on equipment for chemical synthesis, process development, work-up and evaporation.


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Last updated: Jul 14, 2021 at 5:42 AM

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