|
Many chemists are constrained in the laboratory when exploring a wide range of experimental conditions. Due to inherent shortcomings associated with traditional equipment, the ability to discover new synthetic pathways in a timely manner is limited. Reaction temperature, dosing rate, stirring and pH are critical parameters which can’t be truly investigated with traditional synthesis equipment, and often aren’t optimized due to time pressures associated with development. Furthermore, many scientists feel burdened by the requirements to record key process and performance data electronically and synchronize it with other analytical measurements for historical or regulatory purposes. Traditional equipment to support chemical synthesis, such as heating mantles, ice baths and cryostats, combined with standalone dosing funnels and stirrer motors, have limited temperature range, poor control capabilities, are manually intensive and don’t automatically capture and report real-time data as the synthesis proceeds.
Today, researchers are applying effective technology solutions to expand the R&D of innovative molecules and optimized process conditions. Synthesis workstation technologies open new possibilities for control, optimization and reporting of critical process conditions. This paper presents four case studies highlighting how leading pharmaceutical companies are implementing these synthesis workstation technologies and how they impact the performance of the chemical synthesis lab.
Identifying the ideal operating temperature
Identifying the optimal reaction temperature range is often about finding a balance between yield, purity and kinetics. Traditionally, synthesis design space has been limited to three operating temperatures below room temperature: 0 C, -10 C and -78 C. In reality, many reactions operate in a more desirable manner when they are run at temperatures other than these historic conditions. Identifying ideal conditions can be time consuming if parameters are manually set, altered and repeated. However, by leveraging synthesis workstation technology, chemists can gain control and explore innovative reaction conditions by simply operating at the temperatures which are ideal for their chemistry.
|
It’s critical that reaction temperatures can be reliably maintained at the set point and held to a certain range with limited fluctuation. This ensures results are more reproducible, enables comparison between experiments with less repetition required and scale-up has a higher probability of success.
The reaction shown above starts with the activation of the cyanamid [1] by addition of HCl at 60 C where the salt of cyanamid [2] is formed. Once the addition of HCl begins it is important that the temperature is held constant. If the temperature exceed or falls below 60 C, undesired impurity formation occurs from the reaction between cyanamid and the salt of cyanamid [3] or ureum [4].
Figure 2 shows the difference between a manual system using a round bottom flask and a synthesis workstation. The temperature trend for the manual system (red trend, Figure 2) shows the erratic control around 60 C during the reaction due to inconsistent manual temperature control and non-linear HCl dosing. Because of the high fluctuation in the manual system, the temperature increases close to an unsafe area (65 C) where unstable byproducts can be formed. It also makes comparison of experiments difficult.
During HCl dosing, the synthesis workstation enables an extremely stable temperature control at 60 C (green trend, Figure 2), which significantly improves the impurity profile. The stability of the temperature also enables more precise and repeatable results, eliminating repetition and improving comparisons between experiments. Because of the precise results, an exothermic event such as crystallization onset would be easily detected. If an exothermic event had been present in the round bottom flask (red trend), it would’ve been lost in the inherent variability of the temperature control.
|
The beauty of a synthesis workstation is this temperature control is maintained while the system is unattended without the need for ice/oil baths, heating mantles or chillers, so more experimental conditions can be explored to quickly identify ideal conditions and eliminate non-variable candidates.
Gain confidence in the experimental design space
Based on the outcome of the experiments described in the previous example, a central composite Design of Experiment (DoE) was performed studying three parameters: equivalents of NC-NH2, reaction temperature and dosing time. The reaction response was measured by the percentage of guanidine and impurity percentage. Figure 3 and 4 outline the conditions tested in this study.
|
Within this study, center point conditions were repeated in four identical experiments to validate the reproducibility of the experiment setup, control over process parameter and provide confirmation of consistent analytical measurements. By proving the reaction was repeatable, at these conditions scientists gained confidence in the synthesis workstation and analytical sampling and analytical methods. Once process confidence had been established, no additional or repeat experiments were necessary to confirm the central composite DoE set of process parameters.
All these experiments and parameters were programed and controlled using an EasyMax synthesis workstation. This provided safe and repeatable control of dosing, temperature and mixing parameters. A touchscreen-operated setup provided unattended, 24 hr experimentation, resulting in improved laboratory productivity. Between each batch, all experimental data was captured and automatically shared with researchers who simply overlaid batch results in a shared software platform for powerful data analysis and reporting.
|
Based on the outcome of the DoE study, 1.75 equivalents of NC-NH2 with a 4-hr HCl dosing were chosen for scale-up (Figure 5). These conditions balanced process robustness with optimized yield, purity and economic recovery. Faster HCl dosing rates were avoided due to risk of accumulation. 60 C was also chosen, higher temperatures were avoided due to the safety risk and lower temperatures resulted in residual aniline. The process was successfully introduced into production and multiple tons of material was produced with this process, without failure.
Conclusion
Chemists are continually searching for innovative chemistry to develop molecules and process conditions which enable safe and economically viable processes. Due to the increase in molecule complexity, shorter timelines and high scale-up confidence required by industry, new techniques are necessary to develop better chemistry and execute more successful experiments. Synthesis workstations provide a simple and repeatable way to control reaction parameters 24 hrs a day, allowing the chemist to remain focused on improving chemistry. These workstations provide insight to reaction initiation and endpoint, and ensure experiment conditions are automatically recorded making it easy to export data or repeat identical experiments.
• CONFERENCE AGENDA ANNOUNCED:
The highly-anticipated educational tracks for the 2015 R&D 100 Awards & Technology Conference feature 28 sessions, plus keynote speakers Dean Kamen and Oak Ridge National Laboratory Director Thom Mason. Learn more.
